Stemming the Rise of Antibiotic Use for Community-Acquired Acute Respiratory Infections during COVID-19 Pandemic.

At the start of the COVID-19 pandemic, there was an increase in the use of antibiotics for the treatment of community-acquired respiratory tract infection (CA-ARI) in patients admitted for suspected or confirmed COVID-19, raising concerns for misuse. These antibiotics are not under the usual purview of the antimicrobial stewardship unit (ASU). Serum procalcitonin, a biomarker to distinguish viral from bacterial infections, can be used to guide antibiotic recommendations in suspected lower respiratory tract infection. We modified our stewardship approach, and used a procalcitonin-guided strategy to identify "high yield" interventions for audits in patients admitted with CA-ARI. With this approach, there was an increase in the proportion of patients with antibiotics discontinued within 4 days (16.5% vs. 34.9%, p < 0.001), and the overall duration of antibiotic therapy was significantly shorter [7 (6−8) vs. 6 (3−8) days, p < 0.001]. There was a significant decrease in patients with intravenous-to-oral switch of antibiotics to "complete the course" (45.3% vs. 34.4%, p < 0.05). Of the patients who had antibiotics discontinued, none were restarted on antibiotics within 48 h, and there was no-30-day readmission or 30-day mortality attributed to respiratory infection. This study illustrates the importance of the antimicrobial stewardship during the pandemic and the need for ASU to remain attuned to prescriber's practices, and adapt accordingly to address antibiotic misuse to curb antimicrobial resistance.

Therapeutic drug monitoring of meropenem and piperacillin-tazobactam in the Singapore critically ill population - A prospective, multi-center, observational study (BLAST 1).

PURPOSE: To determine percentage of patients with sub-therapeutic beta-lactam exposure in our intensive care units (ICU) and to correlate target attainment with clinical outcomes. MATERIALS AND METHODS: Multi-centre, prospective, observational study was conducted in ICUs from three hospitals in Singapore from July 2016 to May 2018. Adult patients (≥21 years) receiving meropenem or piperacillin-tazobactam were included. Four blood samples were obtained during a dosing interval to measure and determine attainment of therapeutic targets: unbound beta-lactam concentration above (i) minimum inhibitory concentration (MIC) at 40% (meropenem) or 50% (piperacillin) of dosing interval (40-50%fT > MIC) and (ii) 5 × MIC at 100% of dosing interval (100%fT > 5 × MIC). Correlation to clinical outcomes was evaluated using Cox regression. RESULTS: Beta-lactam levels were highly variable among 61 patients, with trough meropenem and piperacillin levels at 21.5 ± 16.8 mg/L and 101.6 ± 81.1 mg/L respectively. Among 85 sets of blood samples, current dosing practices were able to achieve 94% success for 40-50%fT > MIC and 44% for 100%fT > 5 × MIC. Failure to achieve 40-50%fT > MIC within 48 h was significantly associated with all-cause mortality (HR: 9.0, 95% CI: 1.8-45.0), after adjustment for APACHE II score. Achievement of 100%fT > 5 × MIC within 48 h was significantly associated with shorter length of hospital stay. CONCLUSION: Current dosing practices may be suboptimal for ICU patients. Beta-lactam TDM may be useful.

Fused Heterocyclic Systems with an s-Triazine Ring. 34. Development of a Practical Approach for the Synthesis of 5-Aza-isoguanines.

Purine isosteres present excellent opportunities in drug design and development. Using isosteres of natural purines as scaffolds for the construction of new therapeutic agents has been a valid strategy of medicinal chemistry. Inspired by the similarity to isoguanine, we attempted to develop a practical method for the preparation of 5-aza-isoguanines. Several synthetic approaches were explored to establish a robust general protocol for the preparation of these compounds. The significant difference in the reactivity of the C-5 and C-7 electrophilic centers of 1,2,4-triazolo[1,5-a][1,3,5]triazines (5-azapurines) towards nucleophiles was demonstrated. The most practical and general method for the preparation of 5-aza-isoguanines involved a regioselective reaction of ethoxycarbonyl isothiocyanate with a 5-aminotriazole. The intramolecular ring closure of the resulted product followed by the S-methylation afforded 7-methylthio-2-phenyl-1,2,4-triazolo[1,5-a][1,3,5]triazin-5-one, which could be effectively aminated with various amines. The resulted 5-aza-isoguanines resemble a known purine nucleoside phosphorylase inhibitor and could be interesting for further investigations as potential anticancer agents.

Prospective audit and feedback in antimicrobial stewardship: is there value in early reviewing within 48 h of antibiotic prescription?

Antimicrobial stewardship programme (ASP) methodologies are not well defined, with most preferring to wait ≥72-96 h following antibiotic prescription before reviewing patients. However, we hypothesise that early ASP reviews and interventions are beneficial and do not adversely impact patient safety. This study aimed to evaluate the impact of early ASP interventions within 48 h of antibiotic prescription on patient outcomes and safety. A prospective review of ASP interventions made within 48 h of antibiotic prescription in Singapore General Hospital (SGH) from January to December 2012 was conducted. Patient demographics and outcomes were extracted from the database maintained by the ASP team. For culture-directed treatment, there was a shorter mean duration of therapy (DOT) in the accepted group compared with the rejected group (2.26 days vs. 5.56 days; P<0.001). ASP interventions did not alter the length of hospital stay (LOS), 30-day mortality, 14-day Clostridium difficile infection (CDI), 30-day re-admissions and 14-day re-infection (all P>0.05). For empirical treatment, a shorter DOT (3.61 days vs. 6.25 days; P<0.001) and decreased 30-day all-cause mortality (P=0.003) and infection-related mortality (P=0.002) were observed among patients in the accepted group compared with the rejected group. There was no significant difference in LOS, 14-day CDI and 30-day re-admission (all P>0.05). In conclusion, acceptance of early interventions recommended by ASP in SGH was associated with a reduction in DOT without compromising patient safety. This is evident even during empirical therapy when not all clinical information was available.

Echinocandin-induced eosinophilia: a case report.

Drug-induced eosinophilia is difficult to diagnose. Severe organ damage can occur if it is left untreated. Presently, caspofungin is the only echinocandin that has been reported to cause eosinophilia. A patient who developed eosinophilia after exposure to caspofungin and re-challenge with anidulafungin is presented. Eosinophilia resolved upon discontinuation of both drugs.

Nonattenuated Polymyxin B Used for the Treatment of Extreme-Drug Resistant Acinetobacter baumannii-Related Infections in Patients with Preexisting End Stage Renal Failure.

Recent pharmacokinetic studies have suggested that nonrenal clearance predominates the elimination of polymyxin B. We present 2 patients with preexisting end stage renal failure, who were given nonattenuated doses of polymyxin B for the treatment of extreme-drug resistant organism. No evidence of adverse events occurred and microbiological clearance was documented.

The role of international travel in the spread of methicillin-resistant Staphylococcus aureus.

BACKGROUND: Increasing international travel has facilitated the transmission of various multidrug-resistant bacteria-including methicillin-resistant Staphylococcus aureus (MRSA)-across continents. Individuals may acquire MRSA from the community, healthcare facilities, or even from animal exposure. Skin contact with colonized individuals, fomites, or animals during an overseas trip may result in either asymptomatic colonization or subsequent clinically significant MRSA disease. MRSA strains that harbor the Panton-Valentine leucocidin toxin are particularly associated with community transmission and may potentially have enhanced virulence resulting in serious skin and soft tissue infections or even necrotizing pneumonia. More importantly, secondary transmission events upon return from traveling have been documented, leading to potentially detrimental outbreaks within the community or the healthcare setting. We sought to review the existing literature relating to the role of various aspects of travel in the spread of MRSA. Risk factors for acquiring MRSA during travel together with the need for targeted screening of high-risk individuals will also be explored. METHODS: Data for this article were identified via PubMed searches using a combination of search terms: "methicillin resistance," "MRSA," "livestock-associated MRSA," "community-associated MRSA," "travel," and "outbreak." The relevant articles were extensively perused to determine secondary sources of data. RESULTS AND CONCLUSIONS: Our review of the current literature suggests that international travel plays a significant role in the transmission of MRSA, potentially contributing to the replacement of existing endemic MRSA with fitter and more transmissible strains. Therefore, selective and targeted screening of travelers with risk factors for MRSA colonization may be beneficial. Healthcare professionals and patients should be considered for screening if they were to return from endemic areas, with the former group decolonized before returning to patient care work, in order to reduce the transmission of MRSA to vulnerable patient populations.

Direct costs associated with febrile neutropenia in inpatients with hematological diseases in Singapore.

PURPOSE: This prospective cohort study aims to investigate the direct hospitalization costs incurred during febrile neutropenia (FN) in inpatients with underlying hematological conditions and also to elucidate the factors associated with a high cost of managing febrile neutropenia. METHODS: Patients with underlying hematological conditions and documented FN were recruited between October 2008 and February 2011. FN-related costs included all costs incurred from the first day of FN until the last day of antibiotics prescribed. Relevant clinical factors were analyzed using generalized estimating equation models to elucidate the factors that were associated with higher costs of FN. RESULTS: A total of 175 patients were recruited with 303 documented episodes of FN. In non-transplant patients, 75.6 % of the FN episodes occurred. The median and mean cost incurred for each FN episode was USD9,060 (interquartile range = USD5,047-16,631) and USD15,298 (standard deviation ± USD17,459), respectively, accounting for approximately 38 % of the median total hospitalization cost and 37 % of the mean total hospitalization cost. The ward charges (44.1 %) constituted the largest component of the cost, followed by the laboratory charges (27.3 %) and medications (18.7 %), of which antimicrobials constituted 9.6 % of the cost of FN. The factors associated with higher costs of FN include cytomegalovirus reactivation (p < 0.001), longer duration of antibiotics (p < 0.001), lower absolute neutrophil count nadir (p < 0.001), allogeneic stem cell transplantation (p < 0.01), and diagnosis of invasive fungal infection (p < 0.05). CONCLUSION: The economic cost of management of FN in hematology inpatients is considerable and in addition to the overall risk of mortality for this condition. Strategies to reduce FN or ameliorate its costs are essential for this group of patients.

Effects of proactive population-based nephrologist oversight on progression of chronic kidney disease: a retrospective control analysis.

BACKGROUND: Benefits of early nephrology care are well-established, but as many as 40% of U.S. patients with end-stage renal disease (ESRD) do not see a nephrologist before its onset. Our objective was to evaluate the effect of proactive, population-based nephrologist oversight (PPNO) on chronic kidney disease (CKD) progression. METHODS: Retrospective control analysis of Kaiser Permanente Hawaii members with CKD using propensity score matching methods. We matched 2,938 control and case pairs of individuals with stage 3a CKD for the pre-PPNO period (2001-2004) and post-PPNO period (2005-2008) that were similar in other characteristics: age, gender, and the presence of diabetes and hypertension. After three years, we classified the stage outcomes for all individuals. We assessed the PPNO effect across all stages of progression with a χ2-test. We used the z-score test to assess the proportional differences in progression within a stage. RESULTS: The progression within the post-PPNO period was less severe and significantly different from the pre-PPNO period (p = 0.027). Within the stages, there were 2.6% more individuals remaining in 3a in the post-period (95% confidence interval [CI], 1.5% to 3.8%; P value < 0.00001). Progression from 3a to 3b was 2.2% less in the post-period (95% [CI], 0.7% to 3.6%; P value = 0.0017), 3a to 4/5 was 0.2% less (95% CI, 0.0% to 0.87%; P value = 0.26), and 3a to ESRD was 0.24% less (95% CI, 0.0% to 0.66%, P value = 0.10). CONCLUSIONS: Proactive, population-based nephrologist oversight was associated with a statistically significant decrease in progression. With enabling health information technology, risk stratification and targeted intervention by collaborative primary and specialty care achieves population-level care improvements. This model may be applicable to other chronic conditions.

Reinventing electronic support for physicians. A look at Kaiser Permanente's Patient Panel Support Tool and care delivery: Part 1. Interview by John Degaspari.

A Web-based tool that extracts information from the electronic health record helps physicians improve care and manage their entire panel of patients. Two Kaiser Permanente studies examine the effectiveness of the tool in a large, diverse patient population.

Effect of a patient panel-support tool on care delivery.

OBJECTIVE: To evaluate the effect of a patient panel-support tool (PST) on care delivery for diabetes mellitus (DM) and cardiovascular disease (CVD). STUDY DESIGN: Retrospective longitudinal cohort study among primary care providers (PCPs), with 2005 as the preintervention, 2006 as the implementation, and 2007 as the postintervention period. METHODS: We estimated the intervention effect using electronic medical record data and hierarchical linear models. The intervention was a PST displaying "care gaps" and recommendations for glycosylated hemoglobin, low-density lipoprotein cholesterol, and blood pressure screening and control; retinopathy, nephropathy, and foot screening; aspirin, statin, and angiotensin-converting enzyme inhibitor or beta-blocker use; and influenza and pneumococcal vaccination. Participants were qualifying PCPs and health maintenance organizations; patients. Patients had DM or CVD and 12 months of membership (n = 30,273 DM; 26,414 CVD). Main measures were mean percentages of care recommendations that were met by PCPs per patient per month (the care score). RESULTS: From 2005 to 2007, the mean care score (95% confidence interval) increased for both DM and CVD, from 63.5 (62.7, 64.3) to 70.6 (69.8, 71.4) and from 67.9 (67.2, 68.7) to 72.6 (71.9, 73.3), respectively. After adjustments, DM and CVD patients had improvements in the care score of 7.6 and 5.1, respectively, in 2007 compared with 2005 (P < .001). CONCLUSIONS: Delivery of care recommendations for DM and CVD improved after implementation of a PST. More research is necessary to optimize results and determine whether patient outcomes improve.

Computerized prescribing alerts and group academic detailing to reduce the use of potentially inappropriate medications in older people.

OBJECTIVES: To examine the effect of replacing drug-specific computerized prescribing alerts with age-specific alerts on rates of dispensing potentially inappropriate medications in older people and to determine whether group academic detailing enhances the effectiveness of these alerts. DESIGN: Cluster-randomized trial of group academic detailing and interrupted time-series analysis. SETTING: Fifteen clinics of a staff-model health maintenance organization. PARTICIPANTS: Seven practices (113 clinicians, 24,119 patients) were randomly assigned to receive age-specific prescribing alerts plus the academic detailing intervention; eight practices (126 clinicians, 26,805 patients) received alerts alone. Prior implementation of drug-specific alerts established a downward trend in use of target medications that served as the baseline trend for the present study. INTERVENTION: The computerized age-specific alerts occurred at the time of prescribing a targeted potentially inappropriate medication (e.g., tertiary tricyclic amine antidepressants, long-acting benzodiazepines, propoxyphene) and suggested an alternative medication. Clinicians at seven sites were randomized to group academic detailing, an interactive educational program delivering evidence-based information. MEASUREMENTS: Number of target medications dispensed per 10,000 patients per quarter, 2 years before and 1.5 years after the replacement of drug-specific with age-specific alerts. RESULTS: Age-specific alerts resulted in a continuation of the effects of the drug-specific alerts without measurable additional effect (P=.75 for level change), but the age-specific alerts led to fewer false-positive alerts for clinicians. Group academic detailing did not enhance the effect of the alerts. CONCLUSION: Age-specific alerts sustained the effectiveness of drug-specific alerts to reduce potentially inappropriate prescribing in older people and resulted in a considerably decreased burden of the alerts.

Effect of electronic health records in ambulatory care: retrospective, serial, cross sectional study.

OBJECTIVE: To evaluate the effect of implementing comprehensive, integrated electronic health record systems on use and quality of ambulatory care DESIGN: Retrospective, serial, cross sectional study. SETTING: Colorado and Northwest regions of Kaiser Permanente, a US integrated healthcare delivery system. POPULATION: 367,795 members in the Colorado region and 449,728 members in the Northwest region. INTERVENTION: Implementation of electronic health record systems. MAIN OUTCOME MEASURES: Total number of office visits and use of primary care, specialty care, clinical laboratory, radiology services, and telephone contact. Health Plan Employer Data and Information Set to assess quality. RESULTS: Two years after electronic health records were fully implemented, age adjusted rates of office visits fell by 9% in both regions. Age adjusted primary care visits decreased by 11% in both regions and specialty care visits decreased by 5% in Colorado and 6% in the Northwest. All these decreases were significant (P < 0.0001). The percentage of members making > or = 3 visits a year decreased by 10% in Colorado and 11% in the Northwest, and the percentage of members with < or = 2 visits a year increased. In the Northwest, scheduled telephone contact increased from a baseline of 1.26 per member per year to 2.09 after two years. Use of clinical laboratory and radiology services did not change conclusively. Intermediate measures of quality of health care remained unchanged or improved slightly. CONCLUSIONS: Readily available, comprehensive, integrated clinical information reduced use of ambulatory care while maintaining quality and allowed doctors to replace some office visits with telephone contacts. Shifting patterns of use suggest reduced numbers of ambulatory care visits that are inappropriate or marginally productive.

Determination of HER-2 status and chromosome 17 polysomy in breast carcinomas comparing HercepTest and PathVysion FISH assay.

We evaluated and compared 2 HER-2 tests (immunohistochemical analysis [HercepTest, DAKO, Carpinteria, CA] and fluorescence in situ hybridization [FISH]) and assessed chromosome 17 polysomy status in relation to these tests. HER-2 status was obtained in 690 cases. The rinse step in the HercepTest before and after addition of the visualization reagent was 2 minutes in 188 cases and was increased to 5 minutes in 600 cases. HercepTest with both rinse steps was performed on duplicate slides in 98 cases. Chromosome 17 ploidy status based on FISH results was determined in 687 cases. Weak overexpression (2+) of HER-2 protein was not due to gene amplification in a majority of cases (67/76 [88%]). A small subset of breast carcinomas (19/687 [2.8%]) strongly overexpressed (3+) HER-2 protein without gene amplification. The aneuploidy rate was similar in negative and 2+ cases (60/141 [42.5%] and 12/26 [46%]), compared with 86% (18/21) in 3+ cases. The incidence of polysomy 17 in 2+ nonamplified cases (3/67 [4%]) was similar to that seen in negative cases (5.5%), in contrast with 47% (9/19) of 3+ nonamplified cases. Adding a longer rinse step to the HercepTest converted a subset (3/10 [30%]) of weakly positive cases to negative cases. Weak overexpression of HER-2 protein in a majority of cases seems to represent an artifactual staining pattern. Chromosome 17 polysomy is a major factor in strong HER-2 protein overexpression in 3+ nonamplified cases.