Antimicrobial Stewardship in the ICU.

Increasing rates of infection and multidrug-resistant pathogens, along with a high use of antimicrobial therapy, make the intensive care unit (ICU) an ideal setting for implementing and supporting antimicrobial stewardship efforts. Overuse of antimicrobial agents is common in the ICU, as practitioners are challenged daily with achieving early, appropriate empiric antimicrobial therapy to improve patient outcomes. While early antimicrobial stewardship programs focused on the financial implications of antimicrobial overuse, current goals of stewardship programs align closely with those of critical care providers-to optimize patient outcomes, reduce development of resistance, and minimize adverse outcomes associated with antibiotic overuse and misuse such as acute kidney injury and Clostridioides difficile-associated disease. Significant opportunities exist in the ICU for critical care clinicians to support stewardship practices at the bedside, including thoughtful and restrained initiation of antimicrobial therapy, use of biomarkers in addition to rapid diagnostics, Staphylococcus aureus screening, and traditional microbiologic culture and susceptibilities to guide antibiotic de-escalation, and use of the shortest duration of therapy that is clinically appropriate. Integration of critical care practitioners into the initiatives of antimicrobial stewardship programs is key to their success. This review summarizes key components of antimicrobial stewardship programs and mechanisms for critical care practitioners to share the responsibility for antimicrobial stewardship.

Evidence Based Scarce Resource Allocation During the COVID-19 Pandemic: A Case Study of Bamlanivimab Administration in the Emergency Department.

Background: Patients presenting for emergency department (ED) evaluation may be appropriate for treatment with monoclonal antibodies for mild to moderate COVID-19. While many sites have implemented infusion centers for these agents, EDs will continue to evaluate these patients where appropriate identification and efficient infusion of eligible patients is critical. Objectives: Patients receiving bamlanivimab in the EDs of an academic medical center are described. The primary objective was to describe operational metrics and secondary objectives reported clinical outcomes. Methods: Patients receiving bamlanivimab and discharged from the ED were included from November 16, 2020 to January 16, 2021 in the retrospective, observational cohort. Primary outcome was adherence to institutional criteria. Secondary outcomes included ED visit metrics, clinical characteristics, and return visits within 30 days. Risk factors for return visits were assessed with regression. Results: One hundred nineteen patients were included. Most (71%) were diagnosed with COVID-19 during the ED visit and median symptom duration was 3(IQR 2-5) days. Median number of risk factors for progression to severe disease was 2 (IQR 1-2). Thirty percent had a documented abnormal chest x-ray. Institutional criteria adherence was 99.2%. Median time from ED room to bamlanivimab was 4 (IQR 3.1-5.2) hours. Thirty patients had return visit within 30 days; 19 were COVID-19 related. Two multivariable regression models were analyzed for COVID-19 related return visit. Characteristics on ED presentation were considered in Model I: male gender (OR 3.01[0.97-9.31]), age (per 10 years) (OR 1.49[1.05-2.12]), African-American race (OR 3.46[1.09-11.06]), and symptom duration (per day) (OR 1.34[1.05-1.73]). Model II included labs and imaging acquired in ED. In Model II, age (per 10 years) (OR 1.52[1.07-2.16]) and abnormal CXR (OR 5.74[1.95-16.9]) were associated with COVID-19 related return visits. Conclusions: Administration of bamlanivimab to ED patients can be done efficiently, with the potential to reduce COVID-19 related return visits. Age and abnormal imaging were independent predictors of COVID-19 return visits.

Effectiveness of short vs long-course perioperative antibiotics in lung transplant recipients with donor positive respiratory cultures.

Lung transplant recipients are at increased risk for infection in the early postoperative phase, thus perioperative antibiotics are employed. This retrospective study evaluated the efficacy of short- vs long-course perioperative antibiotics in lung transplant patients. Lung transplant patients with donor positive cultures between August 2013 and September 2019 were evaluated, excluding those with cystic fibrosis, death within 14 days and re-transplants. The primary outcome was 30-day freedom from donor-derived respiratory infection. A total of 147 patients were included (57 short vs 90 long-course). Median perioperative antibiotic duration was 6 days in the short-course vs 14 days in the long-course group (P < .0001). Thirty-day freedom from donor-derived respiratory infection was present in 56 (98%) patients in the short-course vs 85 (94%) patients in the long-course group (P = .41). There was no difference in development of Clostridioides difficile infections (P = .41), while cumulative ventilator time and time to post-op extubation were longer in the long-course group (P = .001 and .004, respectively). Among lung transplant recipients with positive donor respiratory cultures, short-course perioperative antibiotics were as effective as long-course antibiotics in preventing donor-derived bacterial respiratory infections.

Oral fluoroquinolones for definitive treatment of gram-negative bacteremia in cancer patients.

PURPOSE: Bloodstream infections (BSI) are significant causes of morbidity and mortality in cancer patients. These patients often receive 10 to 14 days of intravenous (IV) antibiotics. The objective of this study was to compare the outcomes of cancer patients transitioned from IV to oral (PO) therapy compared to continuation of IV treatment. METHODS: This was a single-center, retrospective cohort study of hospitalized adult cancer patients with gram-negative bacteremia. Patients transitioned to a PO fluoroquinolone (FQ) within 5 days were allocated to the IV-to-PO group, while the remaining patients comprised the IV group. The primary outcome was the composite of treatment failure, defined as infection-related readmission, infection recurrence, or inpatient mortality. A multivariable logistic regression model was constructed to account for confounding variables. Secondary outcomes assessed included infection-related length of stay (LOS), hospital LOS, and adverse events, such as Clostridioides difficile infection and catheter-related complications. RESULTS: The IV-to-PO group included 78 patients, while the remaining 133 patients were allocated to the IV group. Differences at baseline included more hematologic malignancy, neutropenia, ICU admissions, and higher Pitt bacteremia scores in the IV group. The rate of treatment failure was significantly higher in the IV group (24% vs 9%; p < 0.01), which persisted in the logistic regression (aOR 3.5, 95% CI 1.3-9.1). The IV-to-PO group had decreased infection-related and hospital length of stay, as well as fewer catheter-related complications. CONCLUSIONS: The use of PO FQ may be considered for the definitive treatment of uncomplicated Enterobacterales BSI in cancer patients.

Effectiveness of fidaxomicin versus oral vancomycin in the treatment of recurrent clostridioides difficile.

WHAT IS KNOWN AND OBJECTIVE: The 2017 IDSA/SHEA Clinical Practice Guidelines for Clostridioides difficile infection (CDI) recommend treating recurrent episodes with fidaxomicin or oral vancomycin, but there is little evidence to support one strategy over another, particularly beyond the first recurrence. The aim of this study was to compare clinical outcomes in patients with recurrent CDI treated with vancomycin vs. fidaxomicin. METHODS: This retrospective study evaluated inpatients with recurrent CDI treated with vancomycin or fidaxomicin between 1 January 2013 and 1 May 2019. The primary outcome was CDI recurrence. Secondary outcomes included re-infection, treatment failure, infection-related length of stay (IRLOS) and in-hospital all-cause mortality (IHACM). The Wilcoxon rank-sum test, Pearson's chi-square test or Fisher's exact test was utilized, as appropriate. A multivariable logistic regression (MLR) model was used to estimate the adjusted odds ratio and 95% confidence interval assessing recurrence while adjusting for confounding variables. A survival analysis was also conducted. RESULTS: 135 patients met the inclusion criteria (35 fidaxomicin vs. 100 vancomycin). There was no difference in CDI recurrence [7 (20%) fidaxomicin vs. 11 (11%) vancomycin, p = 0.18]; this persisted in the MLR model (OR: 0.85 [95% CI 0.27-2.7]) and survival analysis (p = 0.1954). Additionally, there was no difference in re-infection rate (p = 0.73), treatment failure (p = 0.13), IRLOS (p = 0.19) or IHACM (p = 0.65). WHAT IS NEW AND CONCLUSION: This represents the first analysis of CDI recurrence that included patients with >2 prior episodes of CDI. The study found no difference in additional recurrences when patients were treated with oral vancomycin vs fidaxomicin for recurrent CDI. However, the current study is limited by the small sample size available for inclusion. Prospective randomized studies with larger sample sizes are needed to confirm this study's conclusions.

Efficacy of combination therapy versus monotherapy in the treatment of Stenotrophomonas maltophilia pneumonia.

BACKGROUND: Stenotrophomonas maltophilia is intrinsically resistant to several antibiotics, making it potentially challenging to treat. Studies have demonstrated treatment failures and resistance development with monotherapy (MT); however, clinical data are limited with combination therapy (CT). OBJECTIVES: To compare clinical outcomes with CT versus MT for S. maltophilia pneumonia. METHODS: This was a retrospective cohort study of patients admitted between November 2011 and October 2017 with S. maltophilia pneumonia who received at least 48 h of effective therapy. The primary outcome was clinical response after 7 days of effective therapy with CT versus MT. Secondary outcomes included development of a non-susceptible isolate, 30 day microbiological cure, infection recurrence, infection-related mortality and all-cause mortality. The Wilcoxon rank sum test, the Pearson χ2 test and Fisher's exact test were utilized for univariate analyses. A multivariable logistic regression model was used to assess clinical response while adjusting for confounding variables. RESULTS: Of 252 patients with S. maltophilia pneumonia included, 38 received CT and 214 received MT. There was no difference in 7 day clinical response with CT versus MT (47.4% versus 39.7%, P = 0.38), even after controlling for immune status, APACHE II score and polymicrobial pneumonia (adjusted OR 1.51, 95% CI 0.63-3.65). Thirty day microbiological cure (P = 0.44), recurrence (P = 0.53), infection-related mortality (P = 0.19) and isolation of a non-susceptible isolate during or after therapy (P = 1.00 each) were also similar between both groups; however, 30 day all-cause mortality was greater with CT (P = 0.03). CONCLUSIONS: CT had similar rates of clinical efficacy and resistance development compared with MT for S. maltophilia pneumonia.

Impact of a Cost Visibility Tool in the Electronic Medical Record on Antibiotic Prescribing in an Academic Medical Center.

BACKGROUND: Studies evaluating the impact of passive cost visibility tools on antibiotic prescribing are lacking. OBJECTIVE: The objective of this study was to evaluate whether the implementation of a passive antibiotic cost visibility tool would impact antibiotic prescribing and decrease antibiotic spending. METHODS: An efficiency and effectiveness initiative (EEI) was implemented in October 2012. To support the EEI, an antibiotic cost visibility tool was created in June 2013 displaying the relative cost of antibiotics. Using an observational study of interrupted time series design, 3 time frames were studied: pre EEI, post EEI, and post cost visibility tool implementation. The primary outcome was antibiotic cost per 1,000 patient days. Secondary outcomes included case mix index (CMI)-adjusted antibiotic cost per 1,000 patient days and utilization of the cost visibility tool. RESULTS: Initiation of the EEI was associated with a $4,675 decrease in antibiotic cost per 1,000 patient days (P = .003), and costs continued to decrease in the months following EEI (P = .009). After implementation of the cost visibility tool, costs remained stable (P = .844). Despite CMI increasing over time, adjustment for CMI had no impact on the directionality or statistical significance of the results. CONCLUSION: Our study demonstrated a significant and sustained decrease in antibiotic cost per 1,000 patient days when focused medication cost reduction efforts were implemented, but passive cost visibility tool implementation was not associated with additional cost reduction. Antibiotic cost visibility tools may be of most benefit when prior medication cost reduction efforts are lacking or when an active intervention is incorporated.

Nephrotoxicity Risk Factors and Intravenous Vancomycin Dosing in the Immediate Postoperative Period Following Antibiotic-Impregnated Cement Spacer Placement.

BACKGROUND: Several case reports have documented acute kidney injury (AKI) attributable to antibiotic-impregnated cement (AIC) spacers. OBJECTIVES: To identify AKI risk factors among patients who underwent AIC placement and determine whether vancomycin-AIC placement affects systemic vancomycin dosing. METHODS: Phase 1 was a case-control study to identify AKI risk factors among patients who underwent AIC placement. Cases experienced AKI; controls had unchanged renal function. Phase 2 was a retrospective cohort study. Patients who received ≥72 hours of intravenous (IV) vancomycin were divided into 2 groups according to whether they underwent vancomycin-AIC placement. Primary outcome was number of vancomycin dosing changes. RESULTS: Phase 1: Among 26 cases and 74 controls AKI risk factors on univariate and multivariable analysis included exposure to angiotensin-converting-enzyme (ACE) inhibitor exposure within 7 days of AIC placement (42% vs 20%, P = 0.03) and piperacillin-tazobactam within 7 days following AIC placement (31% vs 12%, P = 0.03). Phase 2: Among 53 patients who underwent vancomycin-AIC placement and 104 who underwent another surgery type, vancomycin was adjusted more frequently in patients who underwent vancomycin-AIC placement (28% vs 15%, P = 0.06). CONCLUSIONS: Among patients who undergo AIC placement with vancomycin and/or tobramycin, exposure to ACE inhibitors and piperacillin-tazobactam are associated with increased risk of AKI in the immediate postoperative period. No empirical adjustments to IV vancomycin dosing are necessary in patients undergoing vancomycin-AIC placement.

Is the "low-hanging fruit" worth picking for antimicrobial stewardship programs?

A new antimicrobial stewardship program can be overwhelmed at the breadth of interventions and education required to conduct a successful program. The expression "low-hanging fruit," in reference to stewardship, refers to selecting the most obtainable targets rather than confronting more complicated management issues. These targets include intravenous-to-oral conversions, batching of intravenous antimicrobials, therapeutic substitutions, and formulary restriction. These strategies require fewer resources and less effort than other stewardship activities; however, they are applicable to a variety of healthcare settings, including limited-resource hospitals, and have demonstrated significant financial savings. Our stewardship program found that staged and systematic interventions that focus on obvious areas of need, that is, low hanging fruit, provided early successes in our expanded program with a substantial cumulative cost savings of $832,590.

Risk Factors Associated with Suboptimal Tobramycin Levels in the Medical Intensive Care Unit.

BACKGROUND: Optimal aminoglycoside dosing in critically ill patients represents a challenge for practitioners, especially in the medical intensive care unit (MICU). MICU patients exhibit altered pharmacokinetics due to pathophysiological changes the body undergoes in critical illness, leading to possible treatment failure. The literature surrounding optimal dosing and therapeutic drug monitoring strategies of aminoglycosides in MICU patients is scarce and conflicting. Additionally, only a few studies have investigated risk factors for suboptimal pharmacokinetic target obtainment. Currently, no definitive risk factors have been identified to predict suboptimal aminoglycoside target obtainment in MICU patients. OBJECTIVE: The objective of this study was to determine risk factors for suboptimal pharmacokinetic target obtainment in patients receiving tobramycin in the MICU. METHODS: This single-center, retrospective cohort study included patients 18-89 years old who received at least one 7 mg/kg tobramycin dose in the MICU from January, 1 2015 to September, 30 2020. Patients also had to have at least two detectable drug levels obtained at least one half-life apart following the first tobramycin dose. The primary outcome was to determine the incidence of optimal pharmacokinetic target obtainment, defined as a tobramycin maximum concentration (Cmax) ≥ 10 mcg/ml, and to identify the risk factors for suboptimal (Cmax < 10 mcg/mL) pharmacokinetic target obtainment, in MICU patients. Secondary outcomes were compared between suboptimal and optimal target obtainment in patients with culture confirmed gram-negative infection susceptible to tobramycin. These secondary outcomes included all-cause in-hospital mortality, ICU length of stay (LOS), hospital LOS, and vasopressor duration in those with shock. RESULTS: A total of 230 patients were included in this retrospective study. For the primary outcome, 187 (81.3%) patients achieved optimal target obtainment. Through multivariate logistic regression, female sex and serum albumin < 2.5 g/dL were identified as independent risk factors for suboptimal target obtainment; [OR = 2.14; 95% CI (1.05-4.37), p = 0.037], [OR = 2.50; 95% CI (1.21-5.19), p = 0.014], respectively. Fifty-four (23%) patients had culture-confirmed gram-negative infections susceptible to tobramycin and were included in the subgroup analysis. Of these 54 patients, 11 (20.4%) did not achieve optimal target concentrations. In patients with culture-confirmed gram-negative infection, there was no difference between patients with optimal target obtainment and suboptimal target obtainment in ICU LOS, hospital LOS, all-cause mortality, or vasopressor duration in those with shock. CONCLUSIONS: Among patients receiving their first dose of tobramycin in the MICU, 81.3% obtained an optimal serum concentration. Female sex and serum albumin < 2.5 g/dL were identified as risk factors for suboptimal target obtainment; however, further research is warranted to assess the utility of using these two covariates as risk factors for more aggressive dosing in critically ill MICU patients.

Implementation of an antimicrobial stewardship program in a veterinary medical teaching institution.

Widespread use of antimicrobials in human and veterinary medicine drives the emergence and dissemination of resistant bacteria in human, animal, and environmental reservoirs. The AVMA and FDA Center for Veterinary Medicine have both taken public positions emphasizing the importance of incorporating antimicrobial stewardship in veterinary clinical settings; however, a model for implementing a comprehensive antimicrobial stewardship program in veterinary practice is not readily available. In 2015, The Ohio State University College of Veterinary Medicine began developing a veterinary antimicrobial stewardship program modeled on existing programs in human health-care institutions and the 7 core elements of a successful hospital antimicrobial stewardship program, as defined by the CDC. The program includes comprehensive antimicrobial use guidelines, active environmental surveillance, and enhanced infection control procedures in The Ohio State University Veterinary Medical Center, along with routine monitoring and reporting of antimicrobial prescribing practices and antimicrobial susceptibility patterns of common pathogens isolated from patients and the hospital environment. Finally, programs have been developed to educate clinicians, staff, and students on antimicrobial resistance and appropriate antimicrobial prescribing practices. The antimicrobial stewardship program has been designed to help clinicians and students confidently make judicious antimicrobial use decisions and provide them with actionable steps that can help them act as strong stewards while providing the best care for their patients. This report describes our program and the process involved in developing it, with the intent that the program could serve as a potential model for other veterinary medical institutions.

Clinical Outcomes with Penicillin Versus Alternative ß-Lactams in the Treatment of Penicillin-Susceptible Staphylococcus aureus Bacteremia.

OBJECTIVES: To identify the impact of penicillin versus alternative ß-lactams on clinical outcomes in patients with penicillin-susceptible Staphylococcus aureus (PSSA) bacteremia. DESIGN: Retrospective cohort study. SETTING: Academic medical center. PATIENTS: Adult patients with PSSA bacteremia treated with a ß-lactam as definitive therapy. MEASUREMENTS: The primary outcome was a composite end point of 30-day clinical failure (change in PSSA therapy due to persistent or worsening signs and symptoms, PSSA bacteremia recurrence or persistence, and/or infection-related mortality) in patients treated with penicillin versus alternative ß-lactams. Secondary outcomes included infection-related and hospital length of stay (LOS), 90-day recurrence, 90-day infection-related readmission, 30-day all-cause mortality, adverse drug events (ADEs), and 30-day change in PSSA therapy due to ADEs. A subgroup analysis comparing penicillin, nafcillin, and cefazolin was also conducted. MAIN RESULTS: For the 122 patients who were included, the most common definitive therapies were nafcillin (37%), cefazolin (29%), and penicillin (21%). No difference was found in 30-day clinical failure (4% vs 11%, p=0.46), infection-related LOS (12 days vs 11 days, p=0.39), hospital LOS (12.5 days vs 12 days, p=0.69), 90-day recurrence (p=1.00), 90-day infection-related readmission (p=1.00), or 30-day all-cause mortality (p=0.45) between penicillin and other ß-lactams. The prevalence of ADEs was different among penicillin, nafcillin, and cefazolin (p=0.049), with nafcillin requiring more changes in therapy (p=0.005). CONCLUSIONS: Definitive therapy with penicillin had similar efficacy compared with alternative ß-lactams for the treatment of PSSA bacteremia. However, nafcillin was associated with more ADEs requiring a change in therapy.

Risk of acute kidney injury in critically ill surgical patients with presumed pneumonia is not impacted by choice of methicillin-resistant staphylococcus aureus therapy.

BACKGROUND: Vancomycin and linezolid are standard treatment options for nosocomial methicillin-resistant Staphylococcus aureus (MRSA) pneumonia. While acute kidney injury (AKI) is commonly attributed to vancomycin, existing data has not definitely confirmed vancomycin as an independent risk factor for AKI. AIMS: This study aimed to quantify the incidence of AKI in Surgical Intensive Care Unit (ICU) patients receiving empiric vancomycin or linezolid for nosocomial pneumonia and to identify risk factors for AKI with a focus on MRSA antibiotic therapy. MATERIALS AND METHODS: A retrospective cohort analysis of surgical ICU patients who received at least 48 h of vancomycin or linezolid for pneumonia was performed. Patients who received vancomycin were compared to those who received linezolid with a primary endpoint of AKI as defined by the risk/injury/failure/loss/end-stage renal disease (RIFLE) criteria. A modified RIFLE criteria assessing only changes in serum creatinine was also used. RESULTS: One hundred one patients were evaluated (63 vancomycin and 38 linezolid). AKI occurred in 51 (81.0%) and 32 (84.2%) patients in the vancomycin and linezolid groups (P = 0.79), respectively. Using the modified RIFLE criteria, AKI occurred in 19 (30.2%) and 14 (36.8%) patients in the vancomycin and linezolid groups (P = 0.448). After adjustment for age, diabetes mellitus, Charlson comorbidity index, and concomitant nephrotoxins, there was no difference in risk of AKI between groups (P = 0.773). CONCLUSIONS: Patients who received empiric vancomycin or linezolid for nosocomial pneumonia experienced high, but similar rates of AKI. The results suggest MRSA antibacterial therapy in this setting may not be independently indicative of AKI risk, rather the risk is likely multifactorial.

Impact of rapid identification of Acinetobacter Baumannii via matrix-assisted laser desorption ionization time-of-flight mass spectrometry combined with antimicrobial stewardship in patients with pneumonia and/or bacteremia.

We evaluated the clinical and economic outcomes of matrix-assisted laser desorption ionization time-of-flight mass spectrometry (MALDI-TOF MS) with stewardship intervention in patients with Acinetobacter baumannii (AB) pneumonia and/or bacteremia. 66 patients were included in the pre-intervention group and 53 in the intervention group. The combination of AB identification via MALDI-TOF MS and ID PharmD intervention significantly reduced the median time to effective therapy compared to conventional identification without intervention [77.7 (95% CI: 73.1-84.8) to 36.6 (95% CI: 25.9-50.9) hours (P < 0.0001)]. Rapid organism identification along with ID PharmD intervention was also associated with a 19% increase in clinical cure (15% versus 34%, P = 0.016) and a decreased length of stay during antibiotic therapy (13 [8-18] versus 11 [7-15] days, P = 0.021). No difference in 14-day mortality was observed (20% versus 25%, P = 0.526). Median costs during infection were approximately $6500 less in the intervention group ($49,402 [35,307-86,566] versus $42,872 [26,966-74,506]; P = 0.243). AB identification via MALDI-TOF MS combined with stewardship intervention allows for timely, effective antimicrobial therapy and is associated with increased clinical cure.

An evaluation of acuity adjustment metrics to track medication expense over time.

PURPOSE: The acuity adjustment metric that correlates most closely with actual medication expense at a large, tertiary care academic medical center was investigated. METHODS: This evaluation was conducted at the Ohio State University Wexner Medical Center. All inpatient discharges between July 1, 2012, and March 31, 2013, were included in this study. Patient medical and financial records were used to obtain the diagnosis-related group (DRG) codes and total medication cost for each patient discharge. The primary DRG for each patient was then used to assign the corresponding relative weight (RW) and pharmacy intensity weight (PIW). The correlation between actual and predicted medication expenditure was determined for every DRG for both RW and PIW. Since this compares cost at the DRG level, RW and PIW were used as markers for case-mix index (CMI) and pharmacy intensity score (PIS), respectively. RESULTS: At this single institution, medication cost per discharge was more strongly correlated with PIW (as a marker for PIS) than with RW (as a marker for CMI). Extrapolating these data to hospital-specific values, the results suggest that PIS is more strongly correlated with overall medication expense than CMI and therefore a better adjustment metric for monitoring medication expense over time. CONCLUSION: A single-institution study demonstrated that PIW was more strongly correlated than RW with actual medication expenditure. PIS may be a more accurate acuity metric than CMI for predicting changes in drug expense over time.

Improving the management of candidemia through antimicrobial stewardship interventions.

Candidemia is associated with significant morbidity, mortality, and hospital cost. We conducted a quasi-experimental study to evaluate the impact of an Antimicrobial Stewardship Program (ASP) pharmacist's interventions on time to effective antifungal therapy, in-hospital mortality, infection-related length of stay (LOS), and costs in patients with candidemia. Patients in 2008 (pre-intervention, n = 85) were compared to those in 2010 (post-intervention, n = 88). Time to effective therapy was significantly faster (median 13.5 versus 1.3 hours, P = 0.04) and was administered to more patients in the post-intervention group [67 (88%) versus 80 (99%), P = 0.008]. There was no significant difference in in-hospital mortality [16 (19%) versus 26 (30%) patients, P = 0.11], infection-related LOS [10 (7-15.5) versus 11 (7-17) days, P = 0.68], or hospital costs during candidemia [$25,697 (15,645-42,870) versus $31,457 ($16,399-83,649), P = 0.25]. ASP pharmacist interventions standardized and improved the quality of care of patients with candidemia.

Impact of formulary restriction with prior authorization by an antimicrobial stewardship program.

In an era of increasing antimicrobial resistance and few antimicrobials in the developmental pipeline, many institutions have developed antimicrobial stewardship programs (ASPs) to help implement evidence-based (EB) strategies for ensuring appropriate utilization of these agents. EB strategies for accomplishing this include formulary restriction with prior authorization. Potential limitations to this particular strategy include delays in therapy, prescriber pushback, and unintended increases in use of un-restricted antimicrobials; however, our ASP found that implementing prior authorization for select antimicrobials along with making a significant effort to educate clinicians on criteria for use ensured more appropriate prescribing of these agents, hopefully helping to preserve their utility for years to come.

Peramivir pharmacokinetics in two critically ill adults with 2009 H1N1 influenza A concurrently receiving continuous renal replacement therapy.

STUDY OBJECTIVE: To determine the pharmacokinetics of intravenous peramivir-an investigational neuraminidase inhibitor for the treatment of 2009 H1N1 infection or nonsubtypable influenza A thought to be the 2009 H1N1 virus-in patients concurrently receiving continuous renal replacement therapy (CRRT). DESIGN: Pharmacokinetic analysis. SETTING: Critical care unit at a university-affiliated hospital. PATIENTS: Two critically ill women with 2009 H1N1 influenza A treated with compassionate-use intravenous peramivir administered as a daily infusion of 600 mg over 30 minutes while receiving continuous venovenous hemodiafiltration (CVVHDF), a form of CRRT. MEASUREMENTS AND MAIN RESULTS: Plasma samples were collected from the two patients before and 30 minutes after the fourth (first patient) and ninth (second patient) peramivir infusion to estimate minimum (C(min)) and maximum (C(max)) plasma concentrations, respectively. Two additional postinfusion concentrations were measured from each patient to estimate noncompartmental pharmacokinetic parameters of peramivir while receiving CVVHDF. In the two patients, respectively, C(min) was 2170 and 251 ng/ml, C(max) was 18,400 and 20,300 ng/ml, area under the plasma concentration-time curve from 0-24 hours (AUC(0-24)) was 178,000 and 94,400 ng·hour/ml, drug clearance was 56 and 106 ml/minutes, and plasma half-life was 7.6 and 3.7 hours. The volume of distribution adjusted for ideal body weight at steady state was 0.51 and 0.54 L/kg, respectively. CONCLUSION: The first patient had a slower peramivir plasma clearance compared with the second patient, but both patients had higher peramivir clearances as calculated from AUC(0-24) than those predicted by CRRT. Thus, the dosage of intravenous peramivir was appropriate in these patients. Additional pharmacokinetic data are needed to confirm these results and help guide dosing in patients receiving various forms of CRRT.