Therapeutics for Vancomycin-Resistant Enterococcal Bloodstream Infections.

Vancomycin-resistant enterococci (VRE) are common causes of bloodstream infections (BSIs) with high morbidity and mortality rates. They are pathogens of global concern with a limited treatment pipeline. Significant challenges exist in the management of VRE BSI, including drug dosing, the emergence of resistance, and the optimal treatment for persistent bacteremia and infective endocarditis. Therapeutic drug monitoring (TDM) for antimicrobial therapy is evolving for VRE-active agents; however, there are significant gaps in the literature for predicting antimicrobial efficacy for VRE BSIs. To date, TDM has the greatest evidence for predicting drug toxicity for the three main VRE-active antimicrobial agents daptomycin, linezolid, and teicoplanin. This article presents an overview of the treatment options for VRE BSIs, the role of antimicrobial dose optimization through TDM in supporting clinical infection management, and challenges and perspectives for the future.

Accuracy of antibacterial indication documentation in an electronic medicines management system.

Introduction: Electronic medicines management (EMM) systems are relatively new in the Australian healthcare system. This tertiary hospital network implemented an EMM in 2018, with mandatory documentation of antimicrobial indication when prescribing. Free-text (unrestricted) and pre-defined dropdown (restricted) indications are utilized according to antimicrobial restriction. Objectives: To determine accuracy of antibacterial indication documentation on the medication administration record (MAR) when prescribing and to evaluate factors influencing accuracy of documentation. Methods: A random sample of 400 inpatient admissions of ≥24 h, between March and September 2019, with the first antibacterial prescription per encounter reviewed retrospectively. Demographic and prescription details were extracted. Indication accuracy was assessed by comparing MAR documentation with the medical notes (gold standard). Statistical analysis compared factors associated with accuracy of indication using chi-squared and Fisher's exact tests. Results: Antibacterials were prescribed in 9708 admissions. Of the 400 patients included (60% male; median age 60 years, IQR 40-73), 225 prescriptions were unrestricted and 175 were restricted. Patients were managed by emergency (118), surgical (178) and medical (104) teams. Overall accuracy of antibacterial indication documentation on the MAR was 86%. A higher accuracy rate was found for the unrestricted proportion compared with the restricted proportion (94.2% versus 75.2%; P < 0.0001). Surgical teams had higher accuracy compared with medical and emergency teams (94.4% versus 78.8% versus 79.7%; P < 0.0001). Discussion: Antibacterial indication documentation on the MAR when prescribing demonstrated a high rate of accuracy. Multiple factors influenced this accuracy, which requires further study to determine the impact on accuracy, with a view to improve future EMM builds.

The impact of daptomycin therapeutic drug monitoring on clinical outcomes: a systematic review.

AIM: Daptomycin therapeutic drug monitoring (TDM) is a potentially valuable intervention for a relatively new drug. The aim of this study was to determine whether daptomycin TDM, including dose adjustment where necessary, improves the clinical outcomes of adult patients with Gram-positive infections. METHODS: A systematic review of English-language studies in MEDLINE (Ovid MEDLINE and Epub Ahead of Print, In-process, In-Data-Review & Other Non-Indexed Citations, Daily and Versions), EMBASE via OVID, Cochrane Central Register of Controlled Trials via the OVID platform, Scopus and Web of Science online databases was performed and conducted in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. There was no discrimination on study type or time of publication. STUDY SELECTION: Adults (age ≥18 years) with a Gram-positive infection requiring treatment with daptomycin who received TDM, with subsequent reporting of serum concentrations and dose adjustment where necessary, were included. RESULTS: In total, 2869 studies were identified, of which nine met the inclusion criteria. No studies of daptomycin TDM including a relevant control arm have been published to date. All of the included studies were single-arm observational cohort studies. Broad heterogeneity was observed between the studies in terms of included pathogens, infection types, daptomycin TDM practices, reported clinical outcomes, and reporting of potential confounders. CONCLUSIONS: No studies exploring the efficacy of routine daptomycin TDM on patient-centred outcomes in comparison with fixed dosing regimens have been published to date. This represents a key knowledge gap as opposed to an inherent lack of efficacy. Further well-designed, comparative studies are required to determine the role of daptomycin TDM in patients with Gram-positive infections.

Antibiotic management of urinary tract infections in the post-antibiotic era: a narrative review highlighting diagnostic and antimicrobial stewardship.

BACKGROUND: As one of the most common indications for antimicrobial prescription in the community, the management of urinary tract infections (UTIs) is both complicated by, and a driver of, antimicrobial resistance. OBJECTIVES: To highlight the key clinical decisions involved in the diagnosis and treatment of UTIs in adult women, focusing on clinical effectiveness and both diagnostic and antimicrobial stewardship as we approach the post-antimicrobial era. SOURCES: Literature reviewed via directed PubMed searches and manual searching of the reference list for included studies to identify key references to respond to the objectives. A strict time limit was not applied. We prioritised recent publications, randomised trials, and systematic reviews (with or without meta-analyses) where available. Searches were limited to English language articles. A formal quality assessment was not performed; however, the strengths and limitations of each paper were reviewed by the authors throughout the preparation of this manuscript. CONTENT: We discuss the management of UTIs in ambulatory adult women, with particular focus on uncomplicated infections. We address the diagnosis of UTIs, including the following: definition and categorisation; bedside assessments and point-of-care tests; and the indications for, and use of, laboratory tests. We then discuss the treatment of UTIs, including the following: indications for treatment, antimicrobial sparing approaches, key considerations when selecting a specific antimicrobial agent, specific treatment scenarios, and duration of treatment. We finally outline emerging areas of interest in this field. IMPLICATIONS: The steady increase in antimicrobial resistance among common uropathogens has had a substantial affect on the management of UTIs. Regarding both diagnosis and treatment, the clinician must consider both the patient (clinical effectiveness and adverse effects, including collateral damage) and the community more broadly (population-level antimicrobial selection pressure).

Early antimicrobial stewardship team intervention on appropriateness of antimicrobial therapy in suspected sepsis: a randomized controlled trial.

OBJECTIVES: There has been concern that the imperative to administer rapid antimicrobials in septic patients may result in inappropriate antimicrobial use. We aimed to determine the impact of early antimicrobial stewardship (AMS) team intervention in patients with Medical Emergency Team (MET) calls for suspected sepsis. METHODS: We performed a randomized controlled trial of non-ICU inpatients who had a MET call for suspected sepsis. Patients were randomized to standard care (management of antimicrobial therapy by the treating team) or early targeted intervention (AMS review 48 h post-MET call). The primary outcome was appropriateness of antimicrobial therapy 72 h post-MET call, as determined by a panel of blinded infectious diseases physicians. RESULTS: In total, 90 patients were enrolled; 45 were randomly allocated to the intervention group, and 45 to the control group. More patients in the AMS intervention group were receiving appropriate antimicrobials 72 h following the MET call (67% versus 44%, P = 0.03). In the intervention group, 27 recommendations were made by the AMS team; 74% of recommendations were accepted, including 30% of cases where antimicrobials were discontinued or de-escalated. There were non-significant differences in total duration of antimicrobial therapy (8.7 versus 10.7 days, P = 0.39), sepsis-related ICU-admission rates (13% versus 18%, P = 0.56) and sepsis-related in-hospital mortality (7% versus 9%, P = 0.71) between intervention and control groups, respectively. CONCLUSIONS: AMS team intervention resulted in significant improvement in appropriateness of antimicrobial therapy following MET calls due to suspected sepsis. Targeted AMS review should be implemented to support early antimicrobial de-escalation and optimization in patients with suspected sepsis.

Building on Antimicrobial Stewardship Programs Through Integration with Electronic Medical Records: The Australian Experience.

Antimicrobial stewardship (AMS) is well established in Australian hospitals. Electronic medical record (EMR) implementation has lagged in Australia, with two Healthcare Information and Management Systems Society (HIMSS) Stage 6 hospitals and one Stage 7 hospital as of September 2020. Specific barriers faced by AMS teams with paper-based prescribing and medical records include real-time identification of antimicrobials orders; the ability to prospectively monitor antimicrobial use; and the integration of fundamental point of prescribing AMS principles into routine clinical practice. There are few local guidelines to assist Australian hospitals and AMS teams beyond "out of the box" EMR functionality. EMR implementation has enormous potential to positively impact AMS teams through more efficient workflows and the ability to expand the reach and coverage of AMS activities. There are inevitable limitations associated with EMR implementation that must be considered. In this paper, four Australian hospitals share their experience with EMR roll out, AMS customisation and how they have overcome specific barriers in local AMS practice.

Treatment of invasive IMP-4 Enterobacter cloacae infection in transplant recipients using ceftazidime/avibactam with aztreonam: A case series and literature review.

Infections caused by carbapenemase-producing Enterobacteriaceae (CPE) are an emerging threat in both solid organ and stem cell transplant recipients. Invasive CPE infections in transplant recipients are associated with a high mortality, often due to limited therapeutic options and antibacterial toxicities. One of the most therapeutically challenging group of CPE are the metallo-ß-lactamase (MBL)-producing Gram-negative bacteria, which are now found worldwide, and often need treatment with older, highly toxic antimicrobial regimens. Newer ß-lactamase inhibitors such as avibactam have well-established activity against certain carbapenemases such as Klebsiella pneumoniae carbapenemases (KPC), but have no activity against MBL-producing organisms. Conversely, aztreonam has activity against MBL-producing organisms but is often inactivated by other co-existing ß-lactamases. Here, we report four cases of invasive MBL-CPE infections in transplant recipients caused by IMP-4-producing Enterobacter cloacae who were successfully treated with a new, mechanism-driven antimicrobial combination of ceftazidime/avibactam with aztreonam. This novel antimicrobial combination offers a useful treatment option for high-risk patients with CPE infection, with reduced drug interactions and toxicity.

Global contributions of pharmacists during the COVID-19 pandemic.

Throughout the SARS-CoV-2 (COVID-19) global pandemic, pharmacists were rarely mentioned as essential frontline health care providers by the news media, the public, or politicians. Around the world, pharmacists are working on the frontlines of health care every day providing essential health care services during the pandemic. Pharmacists are medication experts providing patient care in a variety of settings including hospitals, clinics, community pharmacies, long-term care, physician offices, and national and public health. In this paper, we describe how pharmacists from high and low-middle income countries contributed to essential patient care and well-being of the public during the COVID-19 pandemic. While the news media, the public, and politicians often overlooked pharmacists as essential frontline health care providers, we hope that this list of contributions by pharmacists from nine countries in this article can help to change this perspective.

Root Cause Analysis to Identify Medication and Non-Medication Strategies to Prevent Infection-Related Hospitalizations from Australian Residential Aged Care Services.

Infections are leading causes of hospitalizations from residential aged care services (RACS), which provide supported accommodation for people with care needs that can no longer be met at home. Preventing infections and early and effective management are important to avoid unnecessary hospital transfers, particularly in the Australian setting where new quality standards require RACS to minimize infection-related risks. The objective of this study was to examine root causes of infection-related hospitalizations from RACS and identify strategies to limit infections and avoid unnecessary hospitalizations. An aggregate root cause analysis (RCA) was undertaken using a structured local framework. A clinical nurse auditor and clinical pharmacist undertook a comprehensive review of 49 consecutive infection-related hospitalizations from 6 RACS. Data were collected from nursing progress notes, medical records, medication charts, hospital summaries, and incident reports using a purpose-built collection tool. The research team then utilized a structured classification system to guide the identification of root causes of hospital transfers. A multidisciplinary clinical panel assessed the root causes and formulated strategies to limit infections and hospitalizations. Overall, 59.2% of hospitalizations were for respiratory, 28.6% for urinary, and 10.2% for skin infections. Potential root causes of infections included medications that may increase infection risk and resident vaccination status. Potential contributors to hospital transfers included possible suboptimal selection of empirical antimicrobial therapy, inability of RACS staff to establish on-site intravenous access for antimicrobial administration, and the need to access subsidized medical services not provided in the RACS (e.g., radiology and pathology). Strategies identified by the panel included medication review, targeted bundles of care, additional antimicrobial stewardship initiatives, earlier identification of infection, and models of care that facilitate timely access to medical services. The RCA and clinical panel findings provide a roadmap to assist targeting services to prevent infection and limit unnecessary hospital transfers from RACS.

An audit of nitrofurantoin use in three Australian hospitals.

BACKGROUND: International guidelines have recommended the long-acting formulation of nitrofurantoin as first-line treatment for uncomplicated urinary tract infections (UTIs) since 2010. Australian guidelines have only recently listed nitrofurantoin as a first-line agent, but the long-acting formulation is not available. In the setting of increasing multidrug-resistance, the unavailability of the long-acting formulation of nitrofurantoin in Australia, and anecdotal perception of confusion regarding dosing, we audited nitrofurantoin use. METHODS: We performed a retrospective audit of nitrofurantoin use at Alfred Health. All patients dispensed nitrofurantoin from January 2016 to June 2018, as identified from pharmacy dispensing records, were eligible. We used a standardised case report form to extract data from medical records, including dosing regimen and indication. RESULTS: We included 150 patients with 151 nitrofurantoin prescriptions in the analysis, of whom 74% [111/150] were female. Nitrofurantoin was most commonly dispensed for the treatment of UTIs (68% [103/151] versus 32% [48/151] for UTI prophylaxis). For the treatment of uncomplicated UTIs, the most frequently used dose was 100 mg twice daily for five days. In male patients, the 100 mg twice daily for seven days was the most popular regimen. The prophylactic dose of 50 mg once daily was used in women but rarely in men. We did not find evidence of dose adjustment for renal impairment. CONCLUSION: While treatment duration was consistent with guidelines, the dosage and frequency used was often incorrect for the formulation and was not adjusted for renal function. Nitrofurantoin use is likely to increase, so clarification regarding optimal nitrofurantoin dosing regimens may be appropriate.

Improving sepsis care for hospital inpatients using existing medical emergency response systems.

BACKGROUND: Sepsis is a medical emergency; timely management has been shown to reduce mortality. We aimed to improve the care of inpatients who developed sepsis after hospital admission by integrating a sepsis bundle with an existing medical emergency team (MET). METHODS: We performed a before-and-after study at an Australian institution. A multimodal intervention was implemented including formation of a working group, development of a guideline, standard documentation, education, audit and feedback. The primary outcome was the proportion of MET calls where there was compliance with the sepsis resuscitation bundle within one hour of MET call. RESULTS: There was an improvement in completion of the entire resuscitation bundle (OR 2.33, 95%, CI: 1.23 - 4.41) and lactate measurement (OR 2.72, CI: 1.53, 4.84) within one hour of MET call. There was a non-significant reduction in the median time to antibiotic administration in patients where antibiotics were initiated or changed at the MET call (60 mins vs. 44 mins, p = 0.8). In hospital mortality was observed to fall from 22.1% to 11.4%, but after adjusting for age and baseline illness severity this differences was not statistically significant (OR 0.52, CI: 0.23, 1.19, p = 0.12). CONCLUSION: The implementation of a multimodal sepsis bundle and the utilisation of an existing MET call system demonstrated an increase in the overall uptake of a sepsis bundle. This was associated with an observed reduction in all-cause in-hospital mortality, although this difference was not statistically significant after adjustment for confounders. Further interventions with a focus on nursing education and engagement may improve timely antibiotic administration.

A global call from five countries to collaborate in antibiotic stewardship: united we succeed, divided we might fail.

In February, 2016, WHO released a report for the development of national action plans to address the threat of antibiotic resistance, the catastrophic consequences of inaction, and the need for antibiotic stewardship. Antibiotic stewardship combined with infection prevention comprises a collaborative, multidisciplinary approach to optimise use of antibiotics. Efforts to mitigate overuse will be unsustainable without learning and coordinating activities globally. In this Personal View, we provide examples of international collaborations to address optimal prescribing, focusing on five countries that have developed different approaches to antibiotic stewardship-the USA, South Africa, Colombia, Australia, and the UK. Although each country's approach differed, when nurtured, individual efforts can positively affect local and national antimicrobial stewardship programmes. Government advocacy, national guidelines, collaborative research, online training programmes, mentoring programmes, and social media in stewardship all played a role. Personal relationships and willingness to learn from each other's successes and failures continues to foster collaboration. We recommend that antibiotic stewardship models need to evolve from infection specialist-based teams to develop and use cadres of health-care professionals, including pharmacists, nurses, and community health workers, to meet the needs of the global population. We also recommend that all health-care providers who prescribe antibiotics take ownership and understand the societal burden of suboptimal antibiotic use, providing examples of how countries can learn, act globally, and share best antibiotic stewardship practices.

The impact of a multidisciplinary antimicrobial stewardship team on the timeliness of antimicrobial therapy in patients with positive blood cultures: a randomized controlled trial.

BACKGROUND: Antimicrobial stewardship teams play an important role in assisting with the optimization of antimicrobial use in acute care settings. We aimed to determine whether a rapid review by a multidisciplinary antimicrobial stewardship team would improve the timeliness of optimal antimicrobial therapy for patients with positive blood cultures. METHODS: This prospective randomized controlled trial was undertaken in two Australian hospitals. Patients received either standard care (a clinical microbiologist, registrar or laboratory scientist communicating the positive blood culture by phone to the treating doctor) or intervention (standard care plus rapid review by a multidisciplinary antimicrobial stewardship team). Outcomes included time to appropriate and/or active antimicrobial therapy and in-hospital mortality. The trial was registered on the Australian New Zealand Clinical Trials Registry (ACTRN12614000258651). RESULTS: A total of 160 patients were enrolled in this study: 81 in the standard care arm and 79 in the intervention arm. Patients in the intervention arm were commenced earlier on active (HR 8.02, 95% CI: 2.15-29.91) and appropriate antimicrobials (HR 1.95, 95% CI: 1.13-3.38), with a higher proportion of patients allocated to the intervention arm receiving active therapy at 48 h (96% versus 82%) and appropriate therapy at 72 h (70% versus 54%). The majority of patients where the blood culture was a contaminant were not started on antimicrobial therapy, and there were no significant differences in time to cessation of antimicrobial therapy. CONCLUSIONS: Antimicrobial stewardship team review of patients with pathogenic positive blood cultures improved the time to both active and appropriate antimicrobial therapy.

The prevalence and impact of antimicrobial allergies and adverse drug reactions at an Australian tertiary centre.

BACKGROUND: The prevalence and impact of antimicrobial "allergy" labels and Adverse Drug Reactions (ADRs) on antibiotic usage and antimicrobial stewardship initiatives is ill defined. We sought to examine the rate of antimicrobial "allergy labels" at our tertiary referral centre and impacts on antimicrobial usage and appropriateness. METHODS: Two inpatient antimicrobial prevalence surveys were conducted over a 1-week period in November 2013 and 2014 as part of the prospective National Antimicrobial Prescribing Survey (NAPS). Post survey, patients recorded in the NAPS database were assigned to two groups based upon recorded antimicrobial "allergy label" and ADR: (i) Antimicrobial Allergy/ADR (AA) or (ii) No Antimicrobial Allergy/ADR (NAA). Antimicrobial usage and antimicrobial appropriateness were compared between AA and NAA groups. RESULTS: From 509 identified patients the prevalence of an antimicrobial allergy or ADR was 25 %. The prevalence of "allergy labels"/ADR was 10 % (51/509) for penicillin V/G, 5 % (24/509) cephalosporins, 4 % (22/509) trimethroprim-sulfamethoxazole and 3 % (17/509) aminopenicillins. One thousand and seventy antimicrobials were prescribed during the study periods, the median antimicrobial duration was longer in the AA versus NAA group (6 days vs. 4 days; p = 0.018), and proportion of inappropriate antimicrobial prescribing higher in the AA group compared with NAA (29 %; 35/120 vs. 23 %; 86/367, p = 0.22). Oral antimicrobial administration was higher in the NAA than AA group (60 %; 177/297 vs. 46 %; 356/793, p = 0.0001). The proportion of patients that received a ß-lactam was lower in the AA versus NAA group (60 % vs. 79 %, p = 0.0001). CONCLUSIONS: In an Australian tertiary referral centre an antimicrobial "allergy" or ADR label was found to significantly impacted on rate of oral antimicrobial administration, beta-lactam usage, antimicrobial duration and antimicrobial appropriateness.

Antimicrobial Stewardship in Australian Hospitals and Other Settings.

Australia's model of antimicrobial stewardship (AMS) has evolved significantly over recent years, from a long-standing national approach of antimicrobial prescribing guidelines and antimicrobial prescribing restrictions to recent advances including the first National Antimicrobial Resistance Strategy and incorporating mandatory AMS as part of hospital accreditation standards. AMS programs are most commonly found in the hospital setting. Various models are used throughout the country based on the local context and resources available. Programs implemented at Alfred Health and the Royal Brisbane and Women's Hospital represent two successful models in tertiary referral settings that accommodate a general ward setting as well as specialized areas with a high infection burden. Measurement of outcomes related to AMS activities remains poorly standardized, with process indicators such as antimicrobial utilization forming a large proportion of outcome measurement. Presently there is no requirement for any AMS outcome measurements to be reported externally. Point prevalence surveys of appropriateness of prescribing and compliance with prescribing guidelines are widely used at a national level. Despite this, there is still a paucity of published Australian data to support the effect of AMS on patient clinical outcomes. Private hospitals, the community, veterinary medicine and aged care sectors represent an important area for future AMS expansion within Australia. The AMS focus has traditionally been on prescribing restrictions (through the Commonwealth funding agencies); however, recent work has described other areas for improvement and development in both settings. AMS in Australia continues to evolve. The recent development of an Australian strategic plan to link antimicrobial utilization and resistance surveillance with policy represents an important step forward for the future of AMS in Australia.

Prescribing trends before and after implementation of an antimicrobial stewardship program.

OBJECTIVES: Antimicrobial stewardship programs are recommended to reduce antimicrobial resistance by reducing inappropriate use of antimicrobials. We implemented an antimicrobial stewardship program and aimed to evaluate its effect on broad-spectrum antimicrobial use. DESIGN, SETTING AND PARTICIPANTS: Observational study with historical control using interrupted time series analysis conducted in a tertiary referral hospital. Hospital inpatients prescribed restricted antimicrobials for non-standard indications, where approval had expired or without approval. INTERVENTION: Baseline period of 30 months immediately followed by an 18-03 intervention period commencing January 2011. MAIN OUTCOME MEASURES: Number and type of interventions made by antimicrobial stewardship team; monthly rate of use of broad-spectrum antimicrobial agents (in defined daily doses/1000 occupied bed-18s). RESULTS: The antimicrobial stewardship team made 1104 recommendations in 779 patients during the 18-03 intervention period. In 64% of cases, the recommendation was made to cease or de-escalate the antimicrobial therapy, or to change from intravenous to oral therapy. The introduction of the intervention resulted in an immediate 17% (95% CI, 13%-20%) reduction in broad-spectrum antimicrobial use in the intensive care unit and a 10% (95% CI, 4%-16%) reduction in broad-spectrum antimicrobial use outside the intensive care unit. Reductions were particularly seen in cephalosporin and glycopeptide use, although these were partially offset by increases in the use of ß-lactam-ß-lactamase inhibitors. CONCLUSIONS: The introduction of an antimicrobial stewardship program, including postprescription review, resulted in an immediate reduction in broad-spectrum antimicrobial use in a tertiary referral centre. However, the effect of this intervention reduced over time.