Use of leading practices in US hospital antimicrobial stewardship programs.

OBJECTIVE: To determine the proportion of hospitals that implemented 6 leading practices in their antimicrobial stewardship programs (ASPs). Design: Cross-sectional observational survey. SETTING: Acute-care hospitals. PARTICIPANTS: ASP leaders. METHODS: Advance letters and electronic questionnaires were initiated February 2020. Primary outcomes were percentage of hospitals that (1) implemented facility-specific treatment guidelines (FSTG); (2) performed interactive prospective audit and feedback (PAF) either face-to-face or by telephone; (3) optimized diagnostic testing; (4) measured antibiotic utilization; (5) measured C. difficile infection (CDI); and (6) measured adherence to FSTGs. RESULTS: Of 948 hospitals invited, 288 (30.4%) completed the questionnaire. Among them, 82 (28.5%) had <99 beds, 162 (56.3%) had 100-399 beds, and 44 (15.2%) had ≥400+ beds. Also, 230 (79.9%) were healthcare system members. Moreover, 161 hospitals (54.8%) reported implementing FSTGs; 214 (72.4%) performed interactive PAF; 105 (34.9%) implemented procedures to optimize diagnostic testing; 235 (79.8%) measured antibiotic utilization; 258 (88.2%) measured CDI; and 110 (37.1%) measured FSTG adherence. Small hospitals performed less interactive PAF (61.0%; P = .0018). Small and nonsystem hospitals were less likely to optimize diagnostic testing: 25.2% (P = .030) and 21.0% (P = .0077), respectively. Small hospitals were less likely to measure antibiotic utilization (67.8%; P = .0010) and CDI (80.3%; P = .0038). Nonsystem hospitals were less likely to implement FSTGs (34.3%; P < .001). CONCLUSIONS: Significant variation exists in the adoption of ASP leading practices. A minority of hospitals have taken action to optimize diagnostic testing and measure adherence to FSTGs. Additional efforts are needed to expand adoption of leading practices across all acute-care hospitals with the greatest need in smaller hospitals.

Evaluation of an Opt-Out Protocol for Antibiotic De-Escalation in Patients With Suspected Sepsis: A Multicenter, Randomized, Controlled Trial.

BACKGROUND: Sepsis guidelines recommend daily review to de-escalate or stop antibiotics in appropriate patients. This randomized, controlled trial evaluated an opt-out protocol to decrease unnecessary antibiotics in patients with suspected sepsis. METHODS: We evaluated non-intensive care adults on broad-spectrum antibiotics despite negative blood cultures at 10 US hospitals from September 2018 through May 2020. A 23-item safety check excluded patients with ongoing signs of systemic infection, concerning or inadequate microbiologic data, or high-risk conditions. Eligible patients were randomized to the opt-out protocol vs usual care. Primary outcome was post-enrollment antibacterial days of therapy (DOT). Clinicians caring for intervention patients were contacted to encourage antibiotic discontinuation using opt-out language. If continued, clinicians discussed the rationale for continuing antibiotics and de-escalation plans. To evaluate those with zero post-enrollment DOT, hurdle models provided 2 measures: odds ratio of antibiotic continuation and ratio of mean DOT among those who continued antibiotics. RESULTS: Among 9606 patients screened, 767 (8%) were enrolled. Intervention patients had 32% lower odds of antibiotic continuation (79% vs 84%; odds ratio, 0.68; 95% confidence interval [CI], .47-.98). DOT among those who continued antibiotics were similar (ratio of means, 1.06; 95% CI, .88-1.26). Fewer intervention patients were exposed to extended-spectrum antibiotics (36% vs 44%). Common reasons for continuing antibiotics were treatment of localized infection (76%) and belief that stopping antibiotics was unsafe (31%). Thirty-day safety events were similar. CONCLUSIONS: An antibiotic opt-out protocol that targeted patients with suspected sepsis resulted in more antibiotic discontinuations, similar DOT when antibiotics were continued, and no evidence of harm. CLINICAL TRIALS REGISTRATION: NCT03517007.

An Implementation Roadmap for Establishing Remote Infectious Disease Specialist Support for Consultation and Antibiotic Stewardship in Resource-Limited Settings.

Infectious Disease (ID)-trained specialists, defined as ID pharmacists and ID physicians, improve hospital care by providing consultations to patients with complicated infections and by leading programs that monitor and improve antibiotic prescribing. However, many hospitals and nursing homes lack access to ID specialists. Telehealth is an effective tool to deliver ID specialist expertise to resource-limited settings. Telehealth services are most useful when they are adapted to meet the needs and resources of the local setting. In this step-by-step guide, we describe how a tailored telehealth program can be implemented to provide remote ID specialist support for direct patient consultation and to support local antibiotic stewardship activities. We outline 3 major phases of putting a telehealth program into effect: pre-implementation, implementation, and sustainment. To increase the likelihood of success, we recommend actively involving local leadership and other stakeholders in all aspects of developing, implementing, measuring, and refining programmatic activities.

Effects of a Collaborative, Community Hospital Network for Antimicrobial Stewardship Program Implementation.

BACKGROUND: Individual hospitals may lack expertise, data resources, and educational tools to support antimicrobial stewardship programs (ASP). METHODS: We established a collaborative, consultative network focused on hospital ASP implementation. Services included on-site expert consultation, shared database for routine feedback and benchmarking, and educational programs. We performed a retrospective, longitudinal analysis of antimicrobial use (AU) in 17 hospitals that participated for at least 36 months during 2013-2018. ASP practice was assessed using structured interviews. Segmented regression estimated change in facility-wide AU after a 1-year assessment, planning, and intervention initiation period. Year 1 AU trend (1-12 months) and AU trend following the first year (13-42 months) were compared using relative rates (RR). Monthly AU rates were measured in days of therapy (DOT) per 1000 patient days for overall AU, specific agents, and agent groups. RESULTS: Analyzed data included over 2.5 million DOT and almost 3 million patient-days. Participating hospitals increased ASP-focused activities over time. Network-wide overall AU trends were flat during the first 12 months after network entry but decreased thereafter (RR month 42 vs month 13, 0.95, 95% confidence interval [CI]: .91-.99). Large variation was seen in hospital-specific AU. Fluoroquinolone use was stable during year 1 and then dropped significantly. Other agent groups demonstrated a nonsignificant downward trajectory after year 1. CONCLUSIONS: Network hospitals increased ASP activities and demonstrated decline in AU over a 42-month period. A collaborative, consultative network is a unique model in which hospitals can access ASP implementation expertise to support long-term program growth.

Core Recommendations for Antifungal Stewardship: A Statement of the Mycoses Study Group Education and Research Consortium.

In recent years, the global public health community has increasingly recognized the importance of antimicrobial stewardship (AMS) in the fight to improve outcomes, decrease costs, and curb increases in antimicrobial resistance around the world. However, the subject of antifungal stewardship (AFS) has received less attention. While the principles of AMS guidelines likely apply to stewarding of antifungal agents, there are additional considerations unique to AFS and the complex field of fungal infections that require specific recommendations. In this article, we review the literature on AMS best practices and discuss AFS through the lens of the global core elements of AMS. We offer recommendations for best practices in AFS based on a synthesis of this evidence by an interdisciplinary expert panel of members of the Mycoses Study Group Education and Research Consortium. We also discuss research directions in this rapidly evolving field. AFS is an emerging and important component of AMS, yet requires special considerations in certain areas such as expertise, education, interventions to optimize utilization, therapeutic drug monitoring, and data analysis and reporting.

Reducing Fluoroquinolone Use and Clostridioides difficile Infections in Community Nursing Homes Through Hospital-Nursing Home Collaboration.

OBJECTIVE: Nursing homes (NHs) are an important target for antibiotic stewardship (AS). We describe a collaborative model to reduce Clostridioides difficile infections (CDIs) in NHs through optimization of antibiotic use including a reduction in high-risk antibiotics such as fluoroquinolones. DESIGN: Quasi-experimental, pre- and post-intervention study. SETTING AND PARTICIPANTS: Six NHs in Monroe County, NY. METHODS: A hospital-based AS expert team assisted NHs in identifying targets for improving antibiotic use. Interventions included (1) collaboration with a medical director advisory group to develop NH consensus guidelines for testing and treatment of 2 syndromes (urinary tract infections and pneumonia) for which fluoroquinolone use is common, (2) provision of multifaceted NH staff education on these guidelines and education of residents and family members on the judicious use of antibiotics, and (3) sharing facility-specific and comparative antibiotic and CDI data. We used Poisson regression to estimate antibiotic use per 1000 resident days (RD) and CDIs per 10,000 RD, pre- and post-intervention. Segmented regression analysis was used to estimate changes in fluoroquinolone and total antibiotic rates over time. RESULTS: Postintervention, the monthly rate of fluoroquinolone days of therapy (DOT) per 1000 RD significantly decreased by 39% [rate ratio (RR) 0.61, 95% confidence interval (CI) 0.59-0.62, P < .001] across all NHs and the total antibiotic DOT decreased by 9% (RR 0.91, 95% CI 0.90-0.92, P < .001). Interrupted time series analysis of fluoroquinolone and total DOT rates confirmed these changes. The quarterly CDI rate decreased by 18% (RR 0.82, 95% CI 0.68-0.99, P = .042). CONCLUSIONS AND IMPLICATIONS: A hospital-NH partnership with a medical director advisory group achieved a significant reduction in total antibiotic and fluoroquinolone use and contributed to a reduction in CDI incidence. This approach offers one way for NHs to gain access to AS expertise and resources and to standardize practices within the local community.

Denominator Matters in Estimating Antimicrobial Use: A Comparison of Days Present and Patient Days.

Patient days and days present were compared to directly measured person time to quantify how choice of different denominator metrics may affect antimicrobial use rates. Overall, days present were approximately one-third higher than patient days. This difference varied among hospitals and units and was influenced by short length of stay.Infect Control Hosp Epidemiol 2018;39:612-615.

Expert Consensus on Metrics to Assess the Impact of Patient-Level Antimicrobial Stewardship Interventions in Acute-Care Settings.

Antimicrobial stewardship programs (ASPs) positively impact patient care, but metrics to assess ASP impact are poorly defined. We used a modified Delphi approach to select relevant metrics for assessing patient-level interventions in acute-care settings for the purposes of internal program decision making. An expert panel rated 90 candidate metrics on a 9-point Likert scale for association with 4 criteria: improved antimicrobial prescribing, improved patient care, utility in targeting stewardship efforts, and feasibility in hospitals with electronic health records. Experts further refined, added, or removed metrics during structured teleconferences and re-rated the retained metrics. Six metrics were rated >6 in all criteria: 2 measures of Clostridium difficile incidence, incidence of drug-resistant pathogens, days of therapy over admissions, days of therapy over patient days, and redundant therapy events. Fourteen metrics rated >6 in all criteria except feasibility were identified as targets for future development.

Antimicrobial stewardship: philosophy versus practice.

To promote the judicious use of antimicrobials and preserve their usefulness in the setting of growing resistance, a number of policy-making bodies and professional societies have advocated the development of antimicrobial stewardship programs. Although these programs have been implemented at many institutions in the United States, their impact has been difficult to measure. Current recommendations advocate the use of both outcome and process measures as metrics for antimicrobial stewardship. Although patient outcome metrics have the greatest impact on the quality of care, the literature shows that antimicrobial use and costs are the indicators measured most frequently by institutions to justify the effectiveness of antimicrobial stewardship programs. The measurement of more meaningful outcomes has been constrained by difficulties inherent to these measures, lack of funding and resources, and inadequate study designs. Antimicrobial stewardship can be made more credible by refocusing the antimicrobial review process to target specific disease states, reassessing the usefulness of current metrics, and integrating antimicrobial stewardship program initiatives into institutional quality and safety efforts.

Dose ratios between high dose oral morphine or equivalents and oral methadone.

BACKGROUND: Methadone is a commonly used opioid in hospice and palliative care for patients with refractory pain. Various methadone dose conversion methods utilize progressively higher morphine equivalent dose (MED) to methadone dose ratios to compensate for increased methadone potency with escalating opioid doses. OBJECTIVE: The purpose of this study was to determine the dose ratio between equianalgesic doses of high dose oral morphine (daily doses >1200 mg morphine or MED) and oral methadone. METHODS: This study was a retrospective chart review of 324 patients who received methadone at Strong Memorial Hospital or the associated outpatient clinic during a nine-month period in 2011. Ten patients met the study inclusion and exclusion criteria. A Wilcoxon signed-rank test was used to compare the pain scale scores. The Spearman correlation coefficient was used to assess level of correlation between morphine dose and methadone dose. RESULTS: Patients rotated to methadone from high opioid doses had a two-point improvement in median pain scale scores after conversion (p=0.039). However, there was no correlation identified for patients taking daily doses >1200 mg oral morphine or MED prior to methadone rotation (p=0.19). There were no reported methadone adverse effects during the study. CONCLUSIONS: No correlation was identified between high MED doses and methadone at dose stabilization after opioid rotation. A fixed maximum methadone dose of 30 mg/day produced clinically meaningful improvements in pain scores without adverse drug effects. Caution should be exercised before considering rotation to methadone doses higher than 30 mg/day in a patient receiving >1200 mg oral MED/day.

Antimicrobial stewardship programs in community hospitals: the evidence base and case studies.

By controlling and changing how antimicrobial agents are selected and administered, antimicrobial stewardship programs (ASPs) aim to prevent or slow the emergence of antimicrobial resistance; optimize the selection, dosing, and duration of antimicrobial therapy; reduce the incidence of drug-related adverse events; and lower rates of morbidity and mortality, length of hospitalization, and costs. There is an abundant and growing body of evidence demonstrating that ASPs change the quantity and quality of antimicrobial prescriptions; however, measuring whether, when, and how ASPs improve patient outcomes and change patterns of antimicrobial resistance--which is the ultimate goals of ASPs--has been difficult, but the totality of evidence indicates that ASPs are capable of achieving these goals. In this article, we review the existing data on ASPs and their effects on patient care and antimicrobial resistance, as well as strategies for establishing ASPs in different types of hospitals.

In vitro characterization of nebulizer delivery of liposomal amphotericin B aerosols.

Pharmaceutical aerosols have the potential to prevent pulmonary infectious diseases. Liposomal amphotericin B (LAMB, Ambisome, Astellas Pharma US, Deerfield, IL, USA) is approved as an intravenous infusion for empiric treatment of presumed fungal infections in neutropenic, febrile patients, as well as patients infected with Aspergillus, Cryptococcus, and other fungal pathogens. In this study, four different nebulizers were tested for their ability to deliver LAMB in aerodynamic droplet-size ranges relevant to lung deposition by an inertial sampling technique Mass median aerodynamic diameter (MMAD) and fine particle fraction percent <3.3 µm (FPF(3.3)) and <5.8 µm (FPF(5.8)) were determined by cascade impaction during a 2 min sampling period for each of three trials of all nebulizers. The MMADs for all nebulizers ranged from 1.72 ± 0.11 µm to 2.89 ± 0.12 µm; FPF(3.3) and FPF(5.8) were approximately 80% and 90%, respectively. Although all nebulizers appear acceptable for delivery of LAMB, the Pari LC Star and the Aeroeclipse II were considered the best in terms of delivery of aerosol efficiently and the proportion suitable for lung deposition. Additional research on pulmonary delivery and clinical tolerability is warranted.

Pharmacokinetics of posaconazole administered orally or by nasogastric tube in healthy volunteers.

The use of a nasogastric tube is one means of administering antifungal therapy to critically ill patients unable to receive medication via the oral route. This was a phase 1, open-label, single-center, randomized, crossover study of posaconazole administered via nasogastric tube in healthy volunteers. Each subject received two 400-mg single doses of posaconazole, one administered orally and one administered by nasogastric tube, with a 7-day washout period between each dose. Posaconazole was administered 5 to 10 min after subjects received a nutritional supplement. Blood samples for pharmacokinetic analysis were obtained up to 120 h postdose. The analysis of variance estimate of the study population suggests that the posaconazole nasogastric tube administration least-square mean values of observed maximum concentration (C(max)), area under the plasma concentration-time curve (AUC) to the last measurable concentration, and AUC to time infinity were 81%, 76%, and 77%, respectively, of the corresponding oral administration values. The reason for lower C(max) and AUC values when posaconazole is administered via the nasogastric tube route is not known. Oral and nasogastric tube administration of a single 400-mg dose of posaconazole suspension was safe and well tolerated in healthy adult subjects. The incidence and nature of treatment-emergent adverse events were similar with both administration routes, and no serious adverse events or clinically significant laboratory test or vital sign abnormalities were reported. Obtaining plasma posaconazole concentrations may be warranted when posaconazole is given to patients via a nasogastric tube to ensure adequate posaconazole exposure. Strategies that have been shown to enhance posaconazole exposure (such as splitting the dose and minimizing the use of proton pump inhibitors) may also be used.

Mortality and time to extubation in severe hospital-acquired pneumonia.

BACKGROUND: This study examined predictors of in-hospital mortality and time to extubation among patients with acute, severe hospital-acquired pneumonia (HAP) managed in the intensive care unit (ICU). METHODS: Patients with HAP prospectively identified between June 2001 and May 2003 were included in the study if they (1) met the Centers for Disease Control and Prevention's definition for HAP, (2) were treated in the ICU within 1 day of the HAP diagnosis, and (3) required intubation acutely or had a bloodstream infection within 48 hours of the HAP diagnosis. RESULTS: The cohort included 219 patients, 83 of whom died (37.9%). Independent predictors of mortality included cancer (odds ratio [OR] = 4.2; 95% confidence interval [CI] = 1.7 to 10.5), age over 60 years (OR = 2.7; 95% CI = 1.3 to 5.6), APACHE-II score >15 (OR = 2.0; 95% CI = 1.0 to 4.1), and receiving care in the medical ICU (OR = 3.0; 95% CI = 1.1 to 8.2). The following predictors were associated with an increased time to extubation: receipt of vancomycin (1.81-fold increase; P = .001), immunocompromised status (1.92-fold increase; P = .07), and treatment in the surgical or neurosurgical ICU (1.95-fold increase, P = .01; 1.83-fold increase, P = .03). CONCLUSION: Vancomycin was associated with increased time to extubation. Alternatives to vancomycin for treating patients with acute, severe HAP should be studied.

Caspofungin for invasive candidiasis at a tertiary care medical center.

BACKGROUND: Caspofungin is emerging as first-line therapy for invasive candidiasis. Data on the use of caspofungin for treatment for invasive candidiasis are limited to clinical trials and case reports. We report a single-center experience with 104 consecutive courses of caspofungin for the treatment of invasive candidiasis to evaluate a real-world performance of this drug. METHODS: A retrospective chart review of patients receiving caspofungin at a tertiary care medical center was performed. Patient information and microbiologic data were abstracted from patient charts and electronic medical records. RESULTS: Of 241 patients receiving caspofungin for all indications, 122 (51%) had proven invasive candidiasis. There were 104 treatment courses for candidiasis in 99 patients available for review. Bloodstream (66%) and abdominal infections (25%) were the most common sites of infection. Most infections were non-albicans (80/104, 77%; including patients infected with more than one species). Clinical cure rates at the end of therapy were 83% (57/69) for bloodstream infections and 84% (22/26) for abdominal infections. Caspofungin did not clear candidiasis in 14 episodes (microbiologic cure rate 75%, 42/56). CONCLUSIONS: The clinical use of caspofungin has been successful in the treatment of invasive candidiasis, even in patients with prior antifungal exposure. In this unselected review, caspofungin performed similarly as in clinical trials, and clinicians should consider caspofungin as first-line therapy for invasive candidiasis, particularly non-albicans species.

Treatment options for invasive fungal infections.

Clinicians face an increasing occurrence of invasive fungal infections. These are due not only to traditional yeast and mould species but also to rare pathogens that can be difficult to treat. The introduction of new agents has expanded the options for treating common and rare mycotic infections with antifungal efficacy at least equal, and safety far superior, to that of a once-limited choice of therapies. Patients with invasive mycoses frequently have concomitant disorders and require multidrug regimens. Clinicians must be aware of the potential for interactions among agents available for treating invasive mycoses in patients with serious underlying conditions.

Posaconazole.

Invasive fungal infections are occurring with increasing frequency secondary to medical advances in the areas of transplantation, cancer management and autoimmune diseases. Unfortunately, the currently available antifungal armamentarium does not meet the increasing needs of managing infection in these complex patient populations. Posaconazole, a new triazole antifungal agent, is being investigated for its role in treating serious infections due to yeasts and molds. This new drug offers an expanded spectrum of activity over other members of its class. In addition to potent activity against fluconazole-resistant Candida and refractory cases of aspergillosis, posaconazole demonstrates activity against Zygomycetes. Posaconazole is a well-tolerated agent that offers a diminished toxicity profile compared with other currently marketed systemic antifungal agents. Clinical success rates thus far have been promising, although the exact role of this agent in treating and preventing invasive fungal infections is yet to be determined.

Antifungal pharmacotherapy for invasive mould infections.

The incidence of invasive mould infections is increasing and is associated with significant morbidity and mortality. Among the most prevalent of these infections are those caused by Aspergillus and Fusarium species. Invasive disease caused by moulds frequently presents as a pulmonary infection, but haematogenous infection can occur. Some moulds cause cutaneous disease through either direct inoculation of the skin or secondary spread to the skin after dissemination from another body site. Early diagnosis can often be difficult and, unfortunately, diagnosis occurs late in the course of illness in many cases. Treatment options have historically been limited by the need for intravenous administration (amphotericin B), significant toxicities (amphotericin B), lack of reliable in vitro activity (e.g., amphotericin B in Fusarium and Scedosporium apiospermum infections) and relative lack of clinical experience with newer agents. The recent approval of voriconazole (Vfend, Pfizer) introduces a treatment option that demonstrates both in vitro and in vivo activity against a variety of moulds. With the recent development of the new echinocandin class of antifungal agents and newer broad-spectrum azole antifungal agents with in vitro mould activity, there is a renewed emphasis on fungal treatment strategies. Antimould therapy presents challenges in adverse effect avoidance and management, drug interactions and pharmacoeconomic considerations. Furthermore, combination therapy is being explored with these various new antifungal agents. The administration of an optimal fungicidal therapy early in the course of the illness and control of the underlying disease are vital to prevent complications and mortality from these tenacious mycoses.