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Policies that promote conversion of antibiotics from intravenous to oral route administration are considered “low hanging fruit” for hospital antimicrobial stewardship programs. We developed a simple metric based on digestive days of therapy divided by total days of therapy for targeted agents and a method for hospital comparisons. External comparisons may help identify opportunities for improving prospective implementation.

Background Antibiotic Stewardship Programs (ASPs) assist front-line clinicians in synthesizing emerging data and establishing best practices. Our ASP team directly maintained and edited an internal web application, Duke CustomID®, to disseminate updated guideline, policy, and drug information during COVID-19. We aimed to describe website engagement and maintenance during the dynamic pandemic period. Methods We performed a descriptive, time-series analysis using Google Analytics software to measure engagement with Duke CustomID® during a 1-year pre-pandemic period through the Omicron surge: January 2019 to March 2022. We measured total page views (or “hits”), COVID-specific page hits, and days requiring COVID-specific page edits by week. Given fluctuations in hospitalization rates, we defined the primary outcome as the rate of hits divided by total hospitalizations. Weekly data were assessed graphically with positive COVID tests and COVID hospitalizations. We used negative binomial regression to quantify the association between COVID hospitalizations and hit rates and to trend engagement over time, adjusted for seasonality. We stratified data by COVID page and calculated a hit/edit ratio. Results Engagement with CustomID® increased during the pandemic period, especially during surges (Figure). Hits in the pre-pandemic period were median 1707 (range 1165-2354) per week, and hit rates median 1.95 per hospitalization (range 1.40-2.86). Peaks were observed in March 2020 (hit rate 4.59) and January 2022 (hit rate 3.87). On average, for every 100 COVID hospitalizations, the hit rate increased by 0.08 (0.004-0.16, p=0.04). Engagement slowly increased over the study period (relative rate week 1 versus 170: 1.15, 95% confidence interval 1.02-1.28, p=0.02). COVID page edits per week had a median of 2 (range 0-12). Adult Inpatient Guidelines and COVID Monoclonal Antibody pages had highest use (Table). Duke CustomID Hits and Maintenance Efforts over the Pandemic Top: COVID-specific CustomID hits per week (Green), Positive COVID tests per week (Blue) over time Middle: Total custom ID page hits relative to total hospitalizations per week (teal), COVID hospitalizations (Red) Bottom: Number of edits to COVID-specific CustomID pages per week, stratified by management pages and drug pages Several dates of significance are highlighted including the Emergency Use Authorizations (EUA) for remdesivir, the COVID Vaccines, and Paxlovid Duke CustomID COVID-19 Page Hits and Edits COVID specific pages on Duke CustomID with total hits, edits, and ratio over the pandemic Conclusion Our ASP’s website was a highly utilized, practical tool for disseminating practice-changing information during the pandemic. Use increased over time and especially during surges. An electronic reference customized for local practice and rapidly updated by ASPs offers critical support for front-line clinicians. Disclosures Martha B. Adams, M.D., Custom Clinical Decision Support, Inc: Board Member|Custom Clinical Decision Support, Inc: Ownership Interest Richard H. Drew, PharmD MS, American College of Clinical Pharmacists: Publication royalties|Takeda: Advisor/Consultant|UpToDate: publication royalties Rebekah W. Moehring, MD, MPH, FIDSA, FSHEA, UpToDate, Inc.: Author Royalties Michael J. Smith, M.D., M.S.C.E, Merck: Grant/Research Support|Pfizer: Grant/Research Support.

Background Outpatient parenteral antimicrobial therapy (OPAT) is used for patients that require prolonged durations of intravenous (IV) antimicrobials and who are healthy enough to receive the medications in the outpatient setting. While OPAT is both efficacious and cost-effective, hospital readmission rates are high. Durojaiye and colleagues in the UK developed a 30-day unplanned readmission risk prediction model for OPAT patients. Given differences in patient mix and methods of OPAT delivery, we validated the established risk assessment model for Duke University Health System (DUHS) patients receiving OPAT. Methods A retrospective review of 606 OPAT episodes of adult patients who were enrolled in the DUHS OPAT program between July 1, 2019 and February 1, 2020 was conducted. The review captured the 6 risk predictors of the established model: age, Charlson Comorbidity Score, number of admissions in the preceding 12 months, concurrent receipt of more than one IV antimicrobial agent, type of infection, and mode of OPAT delivery. Additional risk predictors were captured: aminoglycoside use, vancomycin use, OPAT delivery in a skilled nursing facility, and history of IV drug abuse. The discriminative ability of the model to predict 30-day unplanned readmission as well as 30-day OPAT-related unplanned readmission was validated with the collected data using scaled Brier score, Hosmer-Lemeshow goodness-of-fit, and area under the receiver operating curve. A logistic regression model fitted with the additional risk factors was conducted to determine their impact on the model. Results When comparing DUHS OPAT patients with those of the UK model, DUHS patients were sicker (mean Charlson Comorbidity Score 3 vs 1), were treated for deeper seated infections, and received OPAT through different modes. Overall the 30-day unplanned readmission rate was 20.0% (94/470), with 59.5% of those being OPAT-related. The UK model was unable to discriminate between patients with readmission and those without, both overall and OPAT-related. The additional risk factors were also non-significant between the groups and the updated model could not predict 30-day readmission risk. Conclusion The UK 30-day unplanned hospital readmission model did not predict patient risk of readmission for the Duke OPAT population. Disclosures Richard H. Drew, PharmD MS, American College of Clinical Pharmacists: Publication royalties|Takeda: Advisor/Consultant|UpToDate: publication royalties.

The purpose of this review is to summarize and evaluate relevant literature on combination antifungal therapy for invasive fungal infections (IFIs). Cryptococcal meningitis has the largest body and highest quality in support of combination therapy with amphotericin B and flucytosine. More recent data in treatment of invasive aspergillosis suggest combination therapy with voriconazole and echinocandins may be effective in select patients. Quality studies are needed to define combination therapy in rare mold infections. Multiple strategies have been employed to optimize treatment of the growing incidence of IFIs. With exceptions as noted above, justification for the use of combination antifungal therapy is most often based on uncontrolled and/or underpowered studies, in vitro data, and case reports.

Background Antimicrobial resistance has been named as one of the top ten threats to public health in the world. Hospital-based antimicrobial stewardship programs (ASPs) can help reduce antimicrobial resistance. The purpose of this study was to determine perceived barriers to the development and implementation of ASPs in tertiary care centers in three low- and middle-income countries (LMICs). Methods Interviews were conducted with 45 physicians at tertiary care hospitals in Sri Lanka (n = 22), Kenya (12), and Tanzania (11). Interviews assessed knowledge of antimicrobial resistance and ASPs, current antimicrobial prescribing practices, access to diagnostics that inform antimicrobial use, receptiveness to ASPs, and perceived barriers to implementing ASPs. Two independent reviewers coded the interviews using principles of applied thematic analysis, and comparisons of themes were made across the three sites. Results Barriers to improving antimicrobial prescribing included prohibitively expensive antimicrobials, limited antimicrobial availability, resistance to changing current practices regarding antimicrobial prescribing, and limited diagnostic capabilities. The most frequent of these barriers in all three locations was limited drug availability. Many physicians in all three sites had not heard of ASPs before the interviews. Improved education was a suggested component of ASPs at all three sites. The creation of guidelines was also recommended, without prompting, by interviewees at all three sites. Although most participants felt microbiological results were helpful in tailoring antibiotic courses, some expressed distrust of laboratory culture results. Biomarkers like erythrocyte sedimentation rate and c-reactive protein were not felt to be specific enough to guide antimicrobial therapy. Despite limited or no prior knowledge of ASPs, most interviewees were receptive to implementing protocols that would include documentation and consultation with ASPs regarding antimicrobial prescribing. Conclusions Our study highlighted several important barriers to implementing ASPs that were shared between three tertiary care centers in LMICs. Improving drug availability, enhancing availability of and trust in microbiologic data, creating local guidelines, and providing education to physicians regarding antimicrobial prescribing are important steps that could be taken by ASPs in these facilities.

Background/Objectives: Our objectives were to determine the prevalence of co-existing bacterial meningitis (BM) and sterile cerebral spinal fluid (CSF) pleocytosis in the presence of Escherichia coli urinary tract infection (UTI) in children age zero days to two years, with the addition of CSF E. coli Polymerase Chain Reaction (PCR) analysis. Subjects/Methods: A retrospective study was conducted at a tertiary referral paediatric hospital from 1/1/2014 to 30/4/2019. Co-existing E. coli BM with UTI was defined as a pure growth E. coli from urine and a CSF culture with pure growth of E. coli and/or positive E. coli PCR. All children with a pure growth of E. coli from a urine sample and a CSF sample taken 48 hours before or after a positive urine culture were included. Further PCR analysis was carried out in cases with CSF pleocytosis. Results: There were 1911 patients that met the definition for an E. coli UTI, of which 314 had a CSF taken within 48 hours. No cases of co-existing E. coli meningitis were identified. Overall, there were 71 (23%) cases of pleocytosis, 57 (80%) of these had further PCR analysis, all of which were E. coli PCR not detected.­ Conclusion: The risk of E. coli UTI and co-existing E. coli BM is low. Routine lumber punctures (LPs) could be avoided in well-appearing infants with a diagnosis of E. coli UTI with the greatest impact seen in children up to 6 months of age. CSF E. coli PCR can help to further reduce the post-test probability of meningitis in the setting of pleocytosis. Funding Statement: None. Declaration of Interests: All authors declare that they have no conflicts of interest. Ethics Approval Statement: The study was reviewed and approved by the CHI Temple Street Scientific and Ethics Committee [REC Reference 19·007].

Background Meningitis caused by methicillin resistant Staphylococcus aureus (MRSA) is rare and often fatal. The recommended treatment for MRSA meningitis, vancomycin, is limited by poor cerebrospinal fluid (CSF) penetration. Ceftaroline fosamil is a novel fifth-generation cephalosporin with potent antibacterial activity in vitro against MRSA. Several case reports in humans suggest that ceftaroline might be a potential treatment option for MRSA meningitis. Our primary objective was to com­pare the efficacy of ceftaroline and vancomycin for the treatment of MRSA meningitis using a rabbit meningitis model. We then characterized CSF drug concentrations over time.Methods Ninety rabbits received a direct intracisternal injection of 5 x 105 CFU S. aureus (MRSA 252). Following a 16-hour incubation period, approximately 0.5ml of CSF was withdrawn via intracisternal aspiration immediately prior to treatment for quantitative bacterial counts and CSF antibiotic concentrations. Rabbits then received (by 1:1:1 random assignment) either no treatment (control group), vancomycin 20 mg/kg at 0 and 12hrs, or ceftaroline 40mg/kg at 0 and 4 hrs via marginal ear vein. CSF collection was repeated every 12 hours for up to 40 hours. All animals were humanely euthanized at 40 hours post inoculation. The primary endpoint (difference in bacterial load [expressed as CFU/mL] for each animal between the initial (T1) and terminal (T3) taps were characterized and compared between groups using the Kruskal-Wallis test. CSF drug concentrations were determined using liquid chromatography with tandem mass spectrometry (LC/MS/MS) assay.ResultsAmong the forty-three evaluable animals with established MRSA meningitis, there was no statistical difference in median CFU observed between the groups in pretreatment CFU counts (p=0.16). Reductions in bacterial load from baseline were 88%, 79% and 75% in the control, ceftaroline and vancomycin-treated groups, respectively. There was no statistical difference observed between vancomycin and either control or ceftaroline at any time point. While animals treated with ceftaroline exhibited a significant increase in clearance rate (log ∆) between T1 and T2 when compared to control (p = 0.019), these differences were no longer statistically significant by T3 (p= 0.43) as CSF ceftaroline concentrations were undetectable by that time point.Conclusions While ceftaroline may be a reasonable alternative to vancomycin for MRSA meningitis, additional animal and clinical studies are required to determine optimal dosing to establish its effectiveness.

Background Antimicrobial stewardship programs (ASPs) are being developed internationally to mitigate the misuse of antimicrobials. An understanding of current practices and prescribing patterns is necessary to determine targets to develop context-specific ASPs in low- and middle-income country (LMIC) hospitals. Methods We conducted a prospective study of patients admitted to the adult medical wards at three LMIC tertiary care centers in 2018- 2019: a 1,800-bed public hospital in Galle, Sri Lanka; a 991-bed public hospital in Eldoret, Kenya; and a 630-bed private hospital in Moshi, Tanzania. Information regarding antimicrobial therapy received during hospitalization, indications for antimicrobial therapy, and duration of antimicrobial use were extracted from the medical record. Results In total, 3150 patients were enrolled: 1297 in Sri Lanka, 750 in Kenya, and 1103 in Tanzania. Antimicrobial use prevalence varied between the three sites, with 56.0% of patients receiving antimicrobials during hospitalization in Sri Lanka, 56.5% in Kenya, and 35.4% in Tanzania. Third-generation cephalosporins were used most frequently in Kenya (70.0%) and Tanzania (73.1%), whereas amoxicillin/ clavulanic acid was used most frequently in Sri Lanka (48.4%). Lower respiratory tract infection was the most common indication for antimicrobial use in all three locations: 37.4% in Sri Lanka, 27.8% in Kenya, and 49.2% in Tanzania. No clear indication for antimicrobial use was documented among 11.6% patients receiving antimicrobials in Sri Lanka, 32.8% in Kenya, and 10.5% in Tanzania. In Tanzania, 8.6% of the patients had documentation of input from the microbiology or infectious diseases teams compared to less than 1% in either Sri Lanka or Kenya. Pertinent culture data related to the primary indication for antimicrobials was present in 16.1% (Sri Lanka), 6.1% (Kenya), and 7.4% (Tanzania). Conclusion Unclear documentation for antimicrobial use was common in all three sites and most patients on antimicrobial therapy did not have pertinent culture data. Improving documentation and the capacity of the local microbiology laboratories could be initial targets for ASPs in these LMIC hospitals. Disclosures All Authors: No reported disclosures

Background: Studies examining relationships between patient-related factors and treatment outcome in patients with candidemia are limited and often based on all-cause mortality. Objective: Our purpose was to examine the impact of concurrent renal replacement therapy (RRT) and other pre-specified factors on treatment outcome among adults with candidemia. Methods: This Institutional Review Board (IRB)-approved, single-center, case-cohort study included patients over 18 years of age admitted to Duke University Hospital between Jun 1, 2013 and Jun 1, 2017 with a blood culture positive for Candida spp. Treatment-, patient-, and disease-specific data were collected, and outcome (success/failure) determined 90 days after the index culture. An odds ratio (OR) and 95% confidence interval (95%CI) were calculated for the following during therapy: receipt of RRT, fluconazole monotherapy regimen, intensive care unit (ICU) stay, and neutropenia. Results: Among the 112 encounters (from 110 unique patients) included, treatment failure occurred in 8/112 (7.1%). Demographics were comparable between outcome groups. Among 12 patients receiving concomitant RRT, only 1 patient failed therapy. With regard to treatment failure, no significant differences were observed with RRT (OR, 1.21; 95%CI, 0.14 – 10.75), fluconazole monotherapy regimen (OR, 1.59; 95%CI, 0.3-8.27), ICU stay (OR, 1.43; 95%CI, 0.32-6.29), and neutropenia (0 treatment failures). Conclusions: Treatment failure, receipt of concomitant RRT, and neutropenia were infrequent in patients undergoing treatment for candidemia. In our cohort, exposure to RRT, a fluconazole monotherapy regimen, ICU stay, or neutropenia during treatment did not impact treatment outcome.

Despite recent advances in both diagnosis and prevention, the incidence of invasive fungal infections continues to rise. Available antifungal agents to treat invasive fungal infections include polyenes, triazoles, and echinocandins. Unfortunately, individual agents within each class may be limited by spectrum of activity, resistance, lack of oral formulations, significant adverse event profiles, substantial drug-drug interactions, and/or variable pharmacokinetic profiles. Isavuconazole, a second-generation triazole, was approved by the US Food and Drug Administration in March 2015 and the European Medicines Agency in July 2015 for the treatment of adults with invasive aspergillosis (IA) or mucormycosis. Similar to amphotericin B and posaconazole, isavuconazole exhibits a broad spectrum of in vitro activity against yeasts, dimorphic fungi, and molds. Isavuconazole is available in both oral and intravenous formulations, exhibits a favorable safety profile (notably the absence of QTc prolongation), and reduced drug-drug interactions (relative to voriconazole). Phase 3 studies have evaluated the efficacy of isavuconazole in the management of IA, mucormycosis, and invasive candidiasis. Based on the results of these studies, isavuconazole appears to be a viable treatment option for patients with IA as well as those patients with mucormycosis who are not able to tolerate or fail amphotericin B or posaconazole therapy. In contrast, evidence of isavuconazole for invasive candidiasis (relative to comparator agents such as echinocandins) is not as robust. Therefore, isavuconazole use for invasive candidiasis may initially be reserved as a step-down oral option in those patients who cannot receive other azoles due to tolerability or spectrum of activity limitations. Post-marketing surveillance of isavuconazole will be important to better understand the safety and efficacy of this agent, as well as to better define the need for isavuconazole serum concentration monitoring.

[Schuts, Emelie C.; van den Bosch, Caroline M.; Prins, Jan M.] Acad Med Ctr, Ctr Infect & Immun Amsterdam CINIMA, Dept Internal Med, Div Infect Dis, Room F4-217,Meibergdreef 9, NL-1105 AZ Amsterdam, Netherlands. [Gyssens, Inge C.; Kullberg, Bart-Jan] Radboud Univ Nijmegen, Med Ctr, Radboud Ctr Infect Dis, Dept Internal Med, NL-6525 ED Nijmegen, Netherlands. [Gyssens, Inge C.] Canisius Wilhelmina Ziekenhuis, Dept Med Microbiol & Infect Dis, Nijmegen, Netherlands. [Gyssens, Inge C.] Hasselt Univ, Hasselt, Belgium. [Leverstein-van Hall, Maurine A.] Bronovo Hosp, Dept Med Microbiol, Leiden, Netherlands. [Natsch, Stephanie] Radboud Univ Nijmegen, Med Ctr, Dept Pharm, NL-6525 ED Nijmegen, Netherlands. [Sebens, Fre] Deventer Ziekenhuis, Dept Med Microbiol & Infect Control, Deventer, Netherlands. [Adams, Martha B.] Duke Univ, Med Ctr, Durham, NC 27710 USA. [Drew, Richard] Duke Univ, Med Ctr, Dept Med, Div Infect Dis, Durham, NC 27710 USA.

Background: There remains variability in both practice and evidence related to optimal initial empiric dosing strategies for vancomycin. Objective: Our primary objective was to describe the percentage of obese patients receiving vancomycin doses consistent with nomogram recommendations achieving targeted initial steady-state serum vancomycin concentrations. Secondary objectives were to describe the primary endpoint in subgroups based on patient weight and estimated creatinine clearance, to describe the rate of supratherapeutic vancomycin accumulation following an initial therapeutic trough concentration, and to describe the rate of vancomycin-related adverse events. Methods: This single-center, IRB-approved, retrospective cohort included adult patients ≥ 100 kilograms total body weight with a body mass index (BMI) >30 kilograms/m2 who received a stable nomogram-based vancomycin regimen and had at least one steady-state vancomycin trough concentration. Data collected included vancomycin regimens and concentrations, vancomycin indication, serum creatinine, and vancomycin-related adverse events. Patients were divided into two cohorts by goal trough concentration: 10-15 mcg/mL and 15-20 mcg/mL. Results: Of 325 patients screened, 85 were included. Goal steady-state concentrations were reached in 42/85 (49.4%) of total patients. Conclusions: Achievement of initial steady-state vancomycin serum concentrations in the present study (approximately 50%) was consistent with the use of published vancomycin dosing nomograms.

Background Penicillin allergy frequently impacts antibiotic choice. As beta-lactams are superior to vancomycin in treating methicillin-susceptible Staphylococcus aureus (MSSA) bacteremia, we examined the effect of reported penicillin allergy on clinical outcomes in patients with MSSA bacteremia. Methods In this retrospective cohort study of adults with MSSA bacteremia admitted to a large tertiary care hospital, outcomes were examined according to reported penicillin allergy. Primary outcomes included 30-day and 90-day mortality rates. Multivariable regression models were developed to quantify the effect of reported penicillin allergy on mortality while adjusting for potential confounders. Results From 2010 to 2015, 318 patients with MSSA bacteremia were identified. Reported penicillin allergy had no significant effect on adjusted 30-day mortality (odds ratio [OR], 0.73; 95% confidence interval [CI], 0.29–1.84; P = .51). Patients with reported penicillin allergy were more likely to receive vancomycin (38% vs 11%, P < .01), but a large number received cefazolin regardless of reported allergy (29 of 66, 44%). Mortality rates were highest among nonallergic patients receiving vancomycin (22.6% vs 7.4% for those receiving beta-lactams regardless of reported allergy, P < .01). In multivariable analysis, beta-lactam receipt was most strongly associated with survival (OR, 0.26; 95% CI, 0.12–0.54). Conclusions Reported penicillin allergy had no significant effect on 30- or 90-day mortality. Non-penicillin-allergic patients receiving vancomycin for treatment of MSSA bacteremia had the highest mortality rates overall. Receipt of a beta-lactam was the strongest predictor of survival. These results underscore the importance of correct classification of patients with penicillin allergy and appropriate treatment with a beta-lactam when tolerated.

Background Skin and soft-tissue infections (SSTI) are a common reason for antimicrobial use in the outpatient and inpatient settings. Inappropriate antimicrobial use for SSTI is common. We determined the prevalence of SSTI and associated inappropriate antimicrobial use among inpatients in Sri Lanka. Methods A point-prevalence study of antimicrobial use was conducted using one-day cross-sectional surveys at five public hospitals in Southern Province, Sri Lanka from Jun-August 2017. Inpatients’ medical records were reviewed for clinical data including antimicrobials prescribed. Inappropriate antimicrobial use was identified as (1) antimicrobial use discordant with guidelines by the Sri Lanka College of Microbiologists (SLCM), and (2) redundant combinations of antimicrobials. Results Of 1,709 surveyed patients, 935 (54.7%) received antimicrobials, of whom 779 (83.3%) had a specified or inferred indication for antimicrobial use. Among patients with an indication for antimicrobial use, SSTI was the second leading indication (181 patients, 23.2%) after lower respiratory tract infection (194, 24.9%). One-third (62, 34.2%) of patients with SSTI had a history of diabetes. Commonly used antimicrobials for SSTI included amoxicillin and clavulanic acid (40.3%), extended-spectrum penicillins (24.9%), and metronidazole (22.1%). inappropriate antimicrobial use was observed in 53.0% of SSTI patients, with redundant antibiotic therapy in 35.9% and antimicrobials discordant with SLCM guidelines in 32.6%. Conclusion SSTI was a common reason for antimicrobial use among inpatients in Sri Lanka, with more than half of patients receiving potentially inappropriate antimicrobial therapy. We identified targets for future antimicrobial stewardship efforts. Disclosures All authors: No reported disclosures.

Background Continuous infusion cefazolin (CI) has been investigated as a means to optimize antibiotic exposure for prophylaxis against SSI, notably in patients undergoing cardiac procedures involving cardiac bypass (CPB). However, data are limited on its impact on late SSIs and adverse events. In 6/16, the Duke University Hospital (DUH) Antimicrobial Stewardship Team implemented a program to promote CI. We compared the incidence of culture-confirmed SSIs through postoperative day 90 (POD90) between patients receiving either intermittent infusion cefazolin (INT) or CI intraoperatively. We also compared the rate of acute kidney injury (AKI) between groups. Methods This retrospective quasi-experimental design included adult and pediatric patients undergoing cardiac surgery at DUH between March 2014 and August 2018 and receiving intraoperative cefazolin (alone or in combination with other antibiotics). Patients were categorized as CI (having received at least 1 intraoperative CI infusion) or INT. Culture-confirmed SSIs utilizing NHSN definitions were recorded and a relative risk (RR) determined. AKI was defined as a ≥0.3 mg/dL rise in serum creatinine within 2 days postoperatively. Results A total of 2,172 unique surgical procedures (from 2,143 unique patients) were included. Comparisons of groups are summarized in Table 1. Rates of SSIs were 1.1% and 1.6% in the CI and INT groups, respectively (RR [95% confidence interval] for CI 0.73, [0.35, 1.52]). AKI was reported in 12.9% and 17.4% of patients, respectively. Conclusion We were unable to detect a difference in late SSIs between intraoperative CI and INT cefazolin. Differences observed between AKI between groups requires further investigation, but likely impacted by confounders, including pre-existing renal dysfunction. Disclosures All authors: No reported disclosures.

Background While data are limited, oral ribavirin (RBV) has been shown to be a cost-effective alternative to aerosolized RBV for the treatment of respiratory syncytial virus (RSV) in immunocompromised patients with significant reductions in acquisition and administration costs. We evaluated the clinical and economic impact of an RBV intervention program at a large, academic medical center. Methods This single-center, retrospective cohort study evaluated hematopoietic cell and solid-organ transplant patients admitted to Duke University Hospital (DUH) with documented or suspected RSV receiving aerosolized and/or oral RBV from July 2013 to April 2018. The ID consult service approval requirement was initiated for aerosolized RBV beginning in October 2015. Education was done at this time to promote oral RBV as the preferred therapy for immunocompromised, RSV-infected adults and children. No restrictions or treatment protocols were in place prior to that time for either formulation. Clinical outcomes, adverse effects, and drug acquisition cost were collected. A cost-avoidance analysis was performed using DUH acquisition cost for actual and alternate RBV therapy. Results A total of 118 treatments (115 unique adult and pediatric patients) were included. Demographics were comparable between groups with and median age was 52 years in the Oral RBV and 61 years in the Aerosol RBV group. The predominant transplant type was lung (62.5% in Oral RBV and 55.6% in Aerosol RBV) followed by hematopoietic (16.7% in Oral RBV and 27% in Aerosol RBV). The median (range) duration of therapy was 4 (1–16) days for oral RBV and 5 (1–23) days for aerosolized RBV. The total cost avoidance was $2,522,915 with oral RBV. Clinical outcomes are summarized in Table 1. Conclusion In our large tertiary care center, the use of oral RBV led to substantial cost avoidance with clinical outcomes comparable to aerosolized RBV in immunocompromised patients. Larger prospective trials evaluating oral RBV for RSV treatment are warranted. Disclosures All authors: No reported disclosures.

Knowledge of local antimicrobial resistance is critical for management of infectious diseases. Community hospitals' compliance with Clinical and Laboratory Standards Institute (CLSI) guidance for creation of cumulative antibiograms is uncertain. This descriptive cohort study of antibiogram reporting practices included community hospitals enrolled in the Duke Infection Control Outreach Network. Cumulative antibiograms from 2012 were reviewed for criteria on reporting practices and compliance with CLSI guidelines. Microbiology personnel were sent a voluntary, electronic survey on antibiogram preparation practices. Data were compiled using descriptive statistics. Thirty-two of 37 (86%) hospitals provided antibiograms; 26 of 37 (70%) also provided survey responses. Twelve (38%) antibiograms specified methods used for compiling data and exclusion of duplicates. Eight (25%) reported only species with >30 isolates. Of the 24 that did not follow the 30-isolate rule, 3 (13%) included footnotes to indicate impaired statistical validity. Twenty (63%) reported at least 1 pathogen-drug combination not recommended for primary or supplemental testing per CLSI. Thirteen (41%) separately reported methicillin-resistant and -susceptible Staphylococcus aureus . Complete compliance with CLSI guidelines was observed in only 3 (9%) antibiograms. Survey respondents' self-assessment of full or partial compliance with CLSI guidelines was 50% and 15%, respectively; 33% reported uncertainty with CLSI guidelines. Full adherence to CLSI guidelines for hospital antibiograms was uncommon. Uncertainty about CLSI guidelines was common. Alternate strategies, such as regional antibiograms using pooled data and educational outreach efforts, are needed to provide reliable and appropriate susceptibility estimates for community hospitals.

Background Invasive infections with Pseudomonas aeruginosa (PA) are associated with significant morbidity and mortality. While risk factors for mortality have been identified, their influence on short-term outcomes impacting treatment selection has not been reported. Objectives The objective of this study was to evaluate the relationship between select patient- and treatment-related factors and short-term outcomes in patients with PA pneumonia and/or bacteremia. Setting Large academic medical center in the United States. Methods This IRB-approved single-center, retrospective case-cohort study included patients >18 years of age with culture-confirmed PA bacteremia and/or pneumonia receiving antimicrobial agent(s) active against PA. Main Outcome Measure Risk of unfavorable short-term treatment result. Results The population consisted of 117 patients (40 [34 %] and 77 [66 %] in the unfavorable and not-unfavorable groups, respectively). Baseline characteristics including age (mean of 63 years), gender (55 % male), Charlson score, creatinine clearance, and body mass index were comparable between groups. Piperacillin/tazobactam was the most common monotherapy antibiotic (46 and 33 % in unfavorable and not-unfavorable groups, respectively). Combination therapy primarily consisted of a beta-lactam plus ciprofloxacin in both unfavorable (10 %) and not-unfavorable (20 %) outcome groups. The preliminary regression model indicated that SIRS, direct ICU admission, and vasopressor therapy were associated with an unfavorable outcome. In addition, patients who received more than two active antimicrobials had a reduced risk of an unfavorable outcome. The final regression model revealed that vasopressor therapy (odds ratio [OR] 6.0; 95 % confidence interval [95 % CI] 2.3, 17) was associated with an unfavorable outcome, while receipt of greater than two active antibiotics was associated with a reduced risk of an unfavorable outcome (OR 0.26; 95 % CI 0.07, 0.83). Conclusions Treatment with more than two agents with activity against PA was associated with a reduced risk of an unfavorable short-term treatment outcome in patients with bacteremia and/or pneumonia.

Purpose The impact of automatic infectious diseases (ID) consultation for inpatients with fungemia at a large academic medical center was studied. Methods In this single-center, retrospective study, the time to appropriate antifungal therapy before and after implementing a policy requiring automatic ID consultation for the management of fungemia for all patients with an inpatient positive blood culture for fungus was examined. The rates of ID consultation; the likelihood of receiving appropriate antifungal therapy; central venous catheter (CVC) removal rates; performance of ophthalmologic examinations; infection-related length of stay (LOS); rates of all-cause inhospital mortality, death, or transfer to an intensive care unit within 7 days of first culture; and inpatient cost of antifungals were also evaluated. Results A total of 173 unique episodes (94 and 79 in the control and intervention groups, respectively) were included. Candida species were the most frequently cultured organisms, isolated from over 90% of patients in both groups. No differences were observed between the control and intervention groups in time to appropriate therapy, infection-related LOS, or time to CVC removal. However, patients in the intervention group were more likely than those in the control group to receive appropriate antifungal therapy ( p = 0.0392), undergo ophthalmologic examination ( p = 0.003), have their CVC removed ( p = 0.0038), and receive ID consultation ( p = 0.0123). Inpatient antifungal costs were significantly higher in the intervention group ( p = 0.0177). Conclusion While automatic ID consultation for inpatients with fungemia did not affect the time to administration of appropriate therapy, improvement was observed for several process indicators, including rates of appropriate antifungal therapy selection, time to removal of CVCs, and performance of ophthalmologic examinations.

Background The widespread uptake of pneumococcal vaccines has substantially reduced the incidence of invasive pneumococcal disease, such that pneumococcal bacteremia in children is now considered a relatively rare event. The objective of this study was to ascertain the clinical utility of a Streptococcus pneumoniae real-time polymerase chain reaction (PCR) assay compared with standard blood culture for the diagnosis of pneumococcal bacteremia in children in the post-vaccine era. Methods A systematic retrospective review of laboratory and patient records from Children's University Hospital, Temple Street, during a 6-year period was performed. Paired blood PCR and blood culture specimens from children younger than 16 years of age were investigated. Statistical analysis was performed to measure the diagnostic accuracy of PCR versus routine bacterial culture techniques. Results More than 1900 PCR test requests were examined from 2010 to 2015, of which 1561 paired PCR and blood culture specimens met criteria for inclusion in the statistical analysis. The PCR assay demonstrated high specificity (99%, confidence interval 95%: 98.81%-99.69%); however, the sensitivity was low compared with that of blood culture (47%, confidence interval 95%: 21.27%-73.41%). Investigation of 10 PCR-positive/culture-negative cases revealed that these cases ranged from definite, probable, and possible significance, indicating a low false positivity rate associated with the assay. Conclusion This study demonstrates the limited utility of blood PCR testing for S. pneumoniae in pediatric patients without radiographic evidence pneumonia or empyema. Moreover, we report that PCR may be a useful diagnostic tool when blood cultures are negative because of antimicrobial therapy before sampling. Given that the incidence of pneumococcal disease has decreased considerably in recent years, justification of S. pneumoniae PCR requisition is necessary. Hence, new guidelines for pediatric pneumococcal blood PCR testing have been introduced at the Irish Meningitis and Sepsis Reference Laboratory.

Objective. To compare pre- and post-intervention test scores assessing insulin injection technique and counseling skills among P1 students with (intervention) or without (control) simulated patients, and to compare counseling checklist and knowledge retention test scores between groups. Methods. This study utilized cluster randomization. In addition to traditional instruction, the intervention group counseled a simulated patient on the use of insulin using the teach-back method. Test score changes from baseline were analyzed via two-sample t-test. Results. The intervention group exhibited a significantly greater increase in knowledge test scores from baseline compared to the control group. Similar changes were seen in post-instruction counseling checklist scores and knowledge retention test scores from baseline. Conclusion. Simulated patient interactions, when added to traditional coursework within a P1 skills lab, improve student counseling aptitude and knowledge retention scores.

To improve the quality and safety of antimicrobial prescribing while minimizing unnecessary cost, antimicrobial stewardship programs (ASPs) require the unique services of a variety of healthcare and ancillary personnel with varied skill sets. At the center of such teams are pharmacists and physicians with specialty training in infectious diseases (ID). The potential implementation of regulations and accreditation standards requiring institutions to have antimicrobial stewardship programs (ASP)s, along with growing evidence to their effectiveness and their increasing presence in different practice settings, are likely to increase the demand for such programs. An assessment of present and potential future antimicrobial stewardship (AS) operations is required to ensure the supply of trained clinicians to meet the growing demand. Presently, the majority of training is achieved either through private study or as part of experiential postgraduate programs. While postgraduate ID-focused programs for pharmacists generally incorporate antimicrobial AS training, such experiences are rarely part of the formalized experience for ID-trained physicians. Although some professional organizations are addressing the perceived lack of individuals with formal postgraduate ID training through certification programs, there are currently no formal regulations or guidelines for such training. It is unlikely the present supply of ID-trained pharmacists will meet the future demands in this area. Therefore, novel strategies (such as access to AS networks, the expanded use of communication and/or information technology, use of alternate personnel, and/or intermittent programs) may increase access to AS-trained clinicians.

In preventing invasive fungal disease (IFD) in patients with acute myelogenous leukemia (AML) or myelodysplastic syndrome (MDS), clinical trials demonstrated efficacy of posaconazole over fluconazole and itraconazole. However, effectiveness of posaconazole has not been investigated in the United States in real-world setting outside the environment of controlled clinical trial. We performed a single-center, retrospective cohort study of 130 evaluable patients ≥18 years of age admitted to Duke University Hospital between 2004 and 2010 who received either posaconazole or fluconazole as prophylaxis during first induction or first reinduction chemotherapy for AML or MDS. The primary endpoint was possible, probable, or definite breakthrough IFD. Baseline characteristics were well balanced between groups, except that posaconazole recipients received reinduction chemotherapy and cytarabine more frequently. IFD occurred in 17/65 (27.0%) in the fluconazole group and in 6/65 (9.2%) in the posaconazole group (P = 0.012). Definite/probable IFDs occurred in 7 (10.8%) and 0 patients (0%), respectively (P = 0.0013). In multivariate analysis, fluconazole prophylaxis and duration of neutropenia were predictors of IFD. Mortality was similar between groups. This study demonstrates superior effectiveness of posaconazole over fluconazole as prophylaxis of IFD in AML and MDS patients. Such superiority did not translate to reductions in 100-day all-cause mortality.

Introduction: Cryptococcal meningoencephalitis (CM) is a rare infection in pediatric patients, which is associated with substantial morbidity and mortality. Since symptoms of this infection are nonspecific, the diagnosis relies on risk assessment and laboratory-confirmed clinical findings. Initial management commonly utilizes amphotericin B and flucytosine, followed by prolonged fluconazole to clear the yeast and prevent relapse. Since no prospective clinical trials have been performed in pediatric patients, much of the data are extrapolated from adult studies and pediatric pharmacokinetic data. This highlights the need for this review and additional studies. Areas covered: Here, the pathophysiology, epidemiology, presentation and treatment of CM in pediatric patients are described. Additionally, the relative safety and pharmacokinetic differences in pharmacologic treatment between pediatric and adult patients are highlighted. Expert opinion: Guidelines for the management of pediatric patients with CM are...

Invasive fungal infections result in significant morbidity and mortality, most notably in immunosuppressed patients. Aerosolized antifungal agents have been utilized primarily as prophylaxis (either alone or in combination with systemic antifungals) in patients at highest risk of invasive infections in attempts to optimize drug delivery while minimizing the potential for systemic toxicity and/or drug interactions. Published clinical experience with aerosolized antifungals most frequently involves various formulations of the polyene amphotericin B in patients undergoing lung transplantation and/or select patients with hematologic malignancy. Adverse events are infrequent and generally limited to dyspnea, dysgeusia, and cough. Existing data suggests lipid-based amphotericin B formulations may be better tolerated than amphotericin B deoxycholate. Published clinical experience with aerosolized antifungals as adjunctive treatment of invasive fungal infections is limited to case reports. Currently, there is insufficient evidence to support use of aerosolized echinocandins and azoles in clinical practice. Outstanding questions regarding comparative efficacy, optimal dose, duration and drug delivery present a continuing challenge when utilizing these agents in clinical practice.

Objective.To validate the utility of a previously published scoring model (Italian) to identify patients infected with community-onset extended-spectrum β-lactamase-producing Enterobacteriaceae (ESBL-EKP) and develop a new model (Duke) based on local epidemiology.Methods.This case-control study included patients 18 years of age or more admitted to Duke University Hospital between January 1, 2008, and December 31, 2010, with culture-confirmed infection due to an ESBL-EKP (cases). Uninfected controls were matched to cases (3 : 1). The Italian model was applied to our patient population for validation. The Duke model was developed through logistic-regression-based prediction scores calculated on variables independently associated with ESBL-EKP isolation. Sensitivities and specificities at various point cutoffs were determined, and determination of the area under the receiver operating characteristic curve (ROC AUC) was performed.Results.A total of 123 cases and 375 controls were identified. Adjusted odds ratios and 95% confidence intervals for variables previously identified in the Italian model were as follows: hospitalization (3.20 [1.62–6.55]), transfer (4.31 [2.15–8.78]), urinary catheterization (5.92 [3.09–11.60]), β-lactam and/or fluoroquinolone therapy (3.76 [2.06–6.95]), age 70 years or more (1.55 [0.79–3.01]), and Charlson Comorbidity Score of 4 or above (1.06 [0.55–2.01]). Sensitivity and specificity were, respectively, more than or equal to 95% and less than or equal to 47% for scores 3 or below and were less than or equal to 50% and more than or equal to 96% for scores 8 or above. The ROC AUC was 0.88. Variables identified in the Duke model were as follows: hospitalization (2.63 [1.32–5.41]), transfer (5.30 [2.67–10.71]), urinary catheterization (6.89 [3.62–13.38]), β-lactam and/or fluoroquinolone therapy (3.47 [1.91–6.41]), and immunosuppression (2.34 [1.14–4.80]). Sensitivity and specificity were, respectively, more than or equal to 94% and less than or equal to 65% for scores 3 or below and were less than or equal to 58% and more than or equal to 95% for scores 8 or above. The ROC AUC was 0.89.Conclusion.While the previously reported model was an excellent predictor of community-onset ESBL-EKP infection, models utilizing factors based on local epidemiology may be associated with improved performance.

Objective.To determine the utility of an antibiogram in predicting the susceptibility of Pseudomonas aeruginosa isolates to targeted antimicrobial agents based on the day of hospitalization the specimen was collected.Design.Single-center retrospective cohort study.Setting.A 750-bed tertiary care medical center.Patients and Methods.Isolates from consecutive patients with at least 1 clinical culture positive for P. aeruginosa from January 1, 2000, to June 30, 2007, were included. A study antibiogram was created by determining the overall percentages of P. aeruginosa isolates susceptible to amikacin, ceftazidime, ciprofloxacin, gentamicin, imipenem-cilastin, piperacillin-tazobactam, and tobramycin during the study period. Individual logistic regression models were created to determine the day of infection after which the study antibiogram no longer predicted susceptibility to each antibiotic.Results.A total of 3,393 isolates were included. The antibiogram became unreliable as a predictor of susceptibility to ceftazidime, imipenem-cilastin, piperacillin-tazobactam, and tobramycin after day 10 and ciprofloxacin after day 15 but longer for gentamicin (day 21) and amikacin (day 28). Time to unreliability of the antibiogram varied for antibiotics based on location of isolation. For example, the time to unreliability of the antibiogram for ceftazidime was 5 days (95% confidence interval [CI], P = .003).Conclusions.The ability of the antibiogram to predict susceptibility of P. aeruginosa decreases as duration of hospitalization increases.

The aim of this study was to review the application of antimicrobial stewardship principles to the management of community-acquired pneumonia (CAP). Data from 14 published clinical studies, meta-analyses and practice guidelines regarding the application of antimicrobial stewardship strategies to the management of CAP were identified and analysed. In the context of CAP, application of stewardship strategies (alone or in combination) has been shown to increase physician awareness of guidelines, improve appropriate antimicrobial use and reduce unnecessary antimicrobial prescribing. In addition, application has had a profound favourable impact on patient outcomes, including decreased 30-day mortality and in-hospital mortality rates, reduced length of hospital stay, reduced treatment failure rates and reduced healthcare costs. Antimicrobial stewardship programmes have been demonstrated to successfully increase the level of appropriate antibiotic prescribing, reduce pathogen resistance and improve clinical outcomes in the management of CAP within hospitals. Studies have also shown that adherence to evidence-based guidelines, even at the level of the individual clinician, can have a profound and positive impact on patient outcomes and healthcare costs. Adherence to evidence-based guidelines can have a profound and positive impact on patient outcomes and healthcare costs.

The introduction of several new antifungals has significantly expanded both prophylaxis and treatment options for invasive fungal infections (IFIs). Relative to amphotericin B deoxycholate, lipid-based formulations of amphotericin B have significantly reduced the incidence of nephrotoxicity, but at a significant increase in drug acquisition cost. Newer, broad-spectrum triazoles (notably voriconazole and posaconazole) have added significantly to both the prevention and treatment of IFIs, most notably Aspergillus spp. (with voriconazole) and the treatment of some emerging fungal pathogens. Finally, a new class of parenteral antifungals, the echinocandins, is employed most frequently against invasive candidal infections. While the role of these newer agents continues to evolve, this review summarizes the activity, safety and clinical applications of agents most commonly employed in the treatment of IFIs.

Background Treatment of candidemia is complex. Studies examining relationships between patient-related factors and treatment outcome are limited, often based on all-cause mortality. Our objectives were to compare concurrent prespecified factors between patients with and without treatment failure among adults with candidemia. Methods This IRB-approved, single-center, case-cohort study included patients >18 years old admitted to Duke University Hospital between June 1, 2013 and June 1, 2017 with a blood culture positive for Candida spp. Treatment-, patient-, and disease-specific data were collected, and outcome (success/failure) determined 90 days after the index culture. An odds ratio (OR) and 95% confidence interval (95% CI) were determined for receipt of renal replacement therapy (RRT), fluconazole-containing regimen, ICU stay, and neutropenia between outcome groups. Results Among the 112 encounters (from 110 unique patients) included, treatment success was observed in 104/112 (92.9%). Demographics were comparable between treatment success and treatment failure groups. Among patients receiving concomitant RRT, 11/12 encounters (91.7%) were successfully treated. No significant differences were observed with regards to treatment failure with a fluconazole-containing regimen (OR, 1.59; 95% CI, 0.3–8.27), ICU stay (OR, 1.43; 95% CI, 0.32–6.29), and neutropenia (OR incomputable due to 0 treatment failures). Conclusion Treatment success occurred in 91.7% of adult patients receiving concomitant RRT while undergoing treatment for candidemia. Treatment with a fluconazole-containing regimen, RRT, ICU stay, and neutropenia did not differ between the treatment outcome groups. Disclosures All authors: No reported disclosures.

Antifungal drug resistance significantly impacts treatment outcomes in patients with invasive fungal infections (IFIs). Although primary (intrinsic) resistance may occur independent of previous therapy, prior concomitant antifungal exposure increases the risk for secondary (acquired) resistance and subsequent colonization or infection with less-susceptible pathogens. Among various pathogen-antifungal combinations, this effect has been best studied clinically with azole exposure and the risk of Candida spp. with reduced susceptibility. The rapid development of secondary resistance to flucytosine in Candida spp. has limited its use as monotherapy. Secondary resistance to amphotericin B is infrequent. In contrast, secondary resistance in Aspergillus spp. is less of a concern. Recent reports of secondary resistance in patients receiving fluconazole for cryptococcal infections may justify susceptibility testing in the setting of prior therapy or treatment failure. Despite numerous patient-focused, drug-focused, and disease-focused strategies to improve treatment outcomes, clinical resistance (manifesting as treatment failures despite adequate antifungal therapy) continues to be problematic in patients with serious IFIs.

Echinocandins have made a significant impact in the treatment of select invasive fungal infections, most notably invasive candidiasis and aspergillosis. However, treatment outcomes for such infections are still less than optimal, prompting an examination of dosing and administration techniques in an attempt to exploit known pharmacodynamic properties and improve outcomes. Echinocandins generally exhibit concentration-dependent, fungicidal activity against Candida spp. and fungistatic activity against Aspergillus spp. However, increasing drug concentrations of echinocandins above the organism's MIC may result in a paradoxical increase in fungal growth as demonstrated in some in vitro and in vivo models (known most commonly as the 'Eagle effect'). Therefore, the potential impact of dose escalations on improving the clinical efficacy of echinocandins based on in vitro and animal models are uncertain and are still being evaluated. In addition, such strategies have to consider the potential for increased treatment-related toxicities and costs. To date, published clinical studies (both superiority and non-inferiority) demonstrating the potential for dose-related improvements in treatment outcomes have been limited to mucocutaneous and oesophageal candidiasis. Further research is needed to determine if a role exists for optimizing echinocandin pharmacodynamics in various clinical settings.

In 2007, the Infectious Diseases Society of America and the Society for Healthcare Epidemiology of America published a document that addressed the major considerations for the justification, description, and conduct of antimicrobial stewardship programs. Our document is intended to continue the dialogue of these formalized programmatic strategies. We briefly review the guidelines, including the two primary strategies (prospective auditing with feedback, and preauthorization), and the supplemental strategies (education, information technology, transitional therapy, de-escalation or streamlining, and dose optimization). Discussions are introduced or furthered in the areas of program goals, barriers and solutions, and outcome measures. Definition and training of infectious diseases pharmacists are presented in detail. We offer keys to future success, which include continued collaboration and expanded use of information technology.

Recently created guidelines for the development of institutional antimicrobial stewardship programs recommend that a pharmacist with infectious diseases training be included as a core member of the antimicrobial stewardship team. However, training and certification requirements for infectious diseases-trained clinical pharmacists have not been established. Although pharmacists have nurtured their interest in infectious diseases by self-directed learning or on-the-job experiences, this mode of training is not considered feasible or sufficient for reliable training of future clinical specialists in infectious diseases. This document, therefore, is forward looking and provides overarching recommendations for future training and certification of pharmacists practicing, mentoring, and educating in infectious diseases pharmacotherapy, with the recognition that full implementation may take several years. We recommend that future pharmacists wishing to obtain a clinical position as an infectious diseases-trained pharmacist should complete a postgraduate year (PGY) 1 residency and a PGY2 residency in infectious diseases, that practitioners become board-certified pharmacotherapy specialists, that a certification examination in infectious diseases be developed, that practitioners maintain a portfolio of educational experiences to maintain qualifications, that current nonaccredited training programs seek accreditation, and that employers and academicians recognize the desirability of these qualifications in hiring decisions.

BACKGROUND: Antimicrobial stewardship programs (ASPs) promote the appropriate use of antimicrobials by selecting the appropriate dose, duration, and route of administration. The appropriate use of antimicrobials has the potential to improve efficacy, reduce treatment-related costs, minimize drug-related adverse events, and limit the potential for emergence of antimicrobial resistance. OBJECTIVE: To summarize ASP tactics that can improve the appropriate use of antimicrobials in the hospital setting. Several measures can be used to implement such programs and gain multidisciplinary support while addressing common barriers. SUMMARY: Implementation of an ASP requires a multidisciplinary approach with an infectious diseases physician and a clinical pharmacist with infectious diseases training as its core team members. As identified by recently published guidelines, 2 proactive strategies for promoting antimicrobial stewardship include: (1) formulary restriction and pre-authorization, and (2) prospective audit with intervention and feedback. Other supplemental strategies involve education, guidelines and clinical pathways, antimicrobial order forms, de-escalation of therapy, intravenous-to-oral (IV-to-PO) switch therapy, and dose optimization. Several barriers exist to successful implementation of ASPs. These include obtaining adequate administrative support and compensation for team members. Gaining physician acceptance can also be challenging if there is a perceived loss of autonomy in clinical decision making. CONCLUSION: ASPs have the potential to reduce antimicrobial resistance, health care costs, and drug-related adverse events while improving clinical outcomes. The efforts and expense required to implement and maintain ASPs are more than justified given their potential benefits to both the hospital and the patient.

Owing to the morbidity and mortality associated with invasive fungal infections, particularly in the immunocompromised host, development of new agents for both prevention and treatment is essential. Posaconazole is a recently approved extended-spectrum triazole available as an oral suspension. It exhibits fungistatic activity against a variety of fungal pathogens. Pharmacokinetic data in special patient populations (such as neutropenic patients with acute myelogenous leukemia or myelodysplastic syndrome, allogeneic hematopoietic stem cell transplant recipients, febrile neutropenic patients and pediatric patients) have been published recently. Controlled clinical trials establish posaconazole's safety and efficacy in infections, such as oropharyngeal candidiasis and prophylaxis against invasive fungal infections. Data are also emerging in the treatment of zygomycosis and selected cases of aspergillosis. Posaconazole is well tolerated during short- and long-term use, with the most commonly reported adverse events being mild-to-moderate gastrointestinal disturbances. Data suggest a relationship between posaconazole plasma concentrations and prophylactic efficacy; however, the role of therapeutic drug monitoring has yet to be completely defined. Since posaconazole is available only as an oral formulation, its use may be limited in critically ill patient populations.

BACKGROUND: Among infectious diseases, community-acquired pneumonia (CAP) is the leading cause of death in the United States and is associated with a substantial economic burden to the health care system. Initiating appropriate empiric therapy can be challenging given elevated resistance rates among Streptococcus pneumoniae strains. OBJECTIVE: To present current recommendations for management of CAP with respect to (a) choosing the appropriate site of care, and (b) antimicrobial selection based on bacterial etiology and the prevalence of resistance. SUMMARY: Mortality prediction tools, such as the PORT (Pneumonia Outcomes Research Team) Severity Index, CURB-65 (Confusion, Urea concentration, Respiratory rate, Blood pressure, and age > 65), or CRB-65 (Confusion, Respiratory rate, Blood pressure, and age > 65), can be invaluable in determining which CAP patients require hospitalization. These tools can help reduce overall costs for CAP by limiting hospitalizations of low-risk patients. S. pneumoniae remains the most common causative pathogen for CAP across all disease severities, and elevated rates of resistance to penicillin and macrolides can hinder selection of appropriate antimicrobial therapy. Antimicrobial resistance can impact clinical outcomes, including increasing the risk of treatment failure and breakthrough bacteremia. Current management guidelines recommend monotherapy with a respiratory fluoroquinolone or combination therapy with a β-lactam and a macrolide (for patients admitted to the general medical ward) or with a β-lactam and either a respiratory fluoroquinolone or a macrolide (for patients admitted to the intensive care unit [ICU] and who do not have risk factors for methicillin-resistant S. aureus or Pseudomonas ). Optimized dosing regimens aim to ensure that pharmacokinetic and pharmacodynamic targets are met to achieve successful clinical outcomes and minimize resistance development. CONCLUSION: Effective management of patients with CAP requires selection of the proper site of care and appropriate empiric antimicrobial. Given the elevated rates of resistance among S. pneumoniae, local resistance patterns must be considered when choosing empiric therapy. J Manag Care Pharm. 2009;15(2)(Suppl):S5-S11 Copyright © 2009, Academy of Managed Care Pharmacy. All rights reserved. THOMAS M. FILE, Jr., MD, MSc, is Professor of Internal Medicine, Master Teacher, and Head, Infectious Disease Section, Northeastern Ohio Universities Colleges of Medicine and Pharmacy, Rootstown, Ohio, and Chief, Infectious Disease Service, Summa Health System, Akron, Ohio. CORRESPONDENCE: Thomas M. File, Jr., MD, MSc, 75 Arch Street, Suite 105, Akron, OH 44304. Tel.: 330.375.3894; Fax: 330.375.6680; E-mail: filet@summa-health.org Author Community-acquired pneumonia (CAP) along with influenza is the leading cause of death among infectious diseases in the United States (and eighth leading cause of death overall).1 Five to 6 million cases occur each year, with persons 65 years or older accounting for about one million cases.2 An estimated 20% of the patients with CAP require admission to the hospital.3 The mortality rate of patients who require admission to the hospital averages 12% overall but increases to 30%-40% for those with severe CAP who require admission to the ICU.2 This compares to a mortality rate of less than 1% among patients with CAP treated on an outpatient basis.4 In addition to the clinical consequence of CAP, the economic cost is extraordinary, with one study estimating the cost for each inpatient episode of CAP to exceed $10,000.3 It is noteworthy that these clinical and economic consequences of CAP occur against the backdrop of effective antimicrobial agents available for the treatment of respiratory tract infections. Many factors must be considered in order to select an appropriate antimicrobial regimen for effectively treating patients with CAP. The first and foremost consideration should be whether an antimicrobial agent is warranted. Viral infections can play a role in a significant portion of patients hospitalized for CAP, with estimates ranging from 1% to 23%.5 Several observational studies have shown that over 50% of the patients with viral respiratory tract infections are inappropriately prescribed antimicrobial agents.6,7 Antimicrobial overuse and inappropriate antimicrobial selection have been associated with increased drug resistance among several respiratory pathogens. In addition, unnecessary use increases cost and potential adverse events. Increasing resistance has made judicious use of antimicrobials an imperative,8 and differentiating viral bronchitis from pneumonia is key in limiting unnecessary antimicrobial use. Unfortunately, there is lack of rapidly available, cost-effective diagnostic tests that reliably differentiate self-limiting viral infections from bacterial infections. However, practice guidelines can offer pragmatic criteria for better antimicrobial usage.9 Once a patient is diagnosed with CAP, optimal management should be based on the site of care, the severity of CAP, the resistance profiles of bacteria, and the pharmacokinetic-pharmacodynamic targets that ensure bacterial eradication. Site of Care Site of care in patients with CAP impacts the overall cost of treatment, the intensity of diagnostic testing, and options for empiric antimicrobial selection. The decision to admit a patient with CAP is based on (a) mortality prediction rules, such as the PORT (Pneumonia Outcomes Research Team) Severity Index (PSI) score or CURB-65 (Confusion, Urea concentration, Respiratory rate, Blood pressure, and age > 65), (b) social circumstances of the patient, and (c) co-existing conditions. Hospitalization. Hospitalization should be considered when (a) patients have pre-existing conditions that may compromise the safety of home care, (b) patients have hypoxemia, (c) patients are unable to take oral medications, or (d) psychosocial factors can