Faculty Bibliography

BACKGROUND:Recent studies indicated that the monosubstituted deoxystreptamine aminoglycoside apramycin is a potent antibiotic against a wide range of MDR Gram-negative pathogens. OBJECTIVES/OBJECTIVE:To evaluate the in vitro activity of apramycin against carbapenem-resistant Klebsiella pneumoniae (CRKp) isolates from New York and New Jersey, and to explore mechanisms of apramycin resistance. METHODS:Apramycin MICs were determined by broth microdilution for 155 CRKp bloodstream isolates collected from 2013 to 2018. MLST STs, wzi capsular types and apramycin resistance gene aac(3')-IV were examined by PCR and Sanger sequencing. Selected isolates were further characterized by conjugation experiments and WGS. RESULTS:Apramycin MIC50/90 values were 8 and >128 mg/L for CRKp isolates, which are much higher than previously reported. Twenty-four isolates (15.5%) were apramycin resistant (MIC ≥64 mg/L) and they were all from the K. pneumoniae ST258 background. The 24 apramycin-resistant K. pneumoniae ST258 strains belonged to six different capsular types and 91.7% of them harboured the apramycin resistance gene aac(3')-IV. Sequencing analysis showed that different ST258 capsular type strains shared a common non-conjugative IncR plasmid, co-harbouring aac(3')-IV and blaKPC. A novel IncR and IncX3 cointegrate plasmid, p59494-RX116.1, was also identified in an ST258 strain, demonstrating how apramycin resistance can be spread from a non-conjugative plasmid through cointegration. CONCLUSIONS:We described a high apramycin resistance rate in clinical CRKp isolates in the New York/New Jersey region, mainly among the epidemic K. pneumoniae ST258 strains. The high resistance rate in an epidemic K. pneumoniae clone raises concern regarding the further optimization and development of apramycin and apramycin-like antibiotics.

OPINION STATEMENT/UNASSIGNED:Treatment sequencing in early-stage breast cancer has significantly evolved in recent years, particularly in the triple negative (TNBC) and human epidermal growth factor receptor 2 (HER2)-positive subsets. Instead of surgery first followed by chemotherapy, several clinical trials showed benefits to administering systemic chemotherapy (and HER2-targeted therapies) prior to surgery. These benefits include more accurate prognostic estimates based on the extent of residual cancer that can also guide adjuvant treatment, and frequent tumor downstaging that can lead to smaller surgeries in patients with large tumors at diagnosis. Patients with extensive invasive residual cancer after neoadjuvant therapy are at high risk for disease recurrence, and two pivotal clinical trials, CREATE-X and KATHERINE, demonstrated improved recurrence free survival with adjuvant capecitabine and ado-trastuzumab-emtansine (T-DM1) in TNBC and HER2-positive residual cancers, respectively. Patients who achieve pathologic complete response (pCR) have excellent long-term disease-free survival regardless of what chemotherapy regimen induced this favorable response. This allows escalation or de-escalation of adjuvant therapy: patients who achieved pCR could be spared further chemotherapy, while those with residual cancer could receive additional chemotherapy postoperatively. Ongoing clinical trials are testing this strategy (CompassHER2-pCR: NCT04266249). pCR also provides an opportunity to assess de-escalation of locoregional therapies. Currently, for patients with residual disease in the lymph nodes (ypN+), radiation therapy entails coverage of the undissected axilla, and may include supra/infraclavicular/internal mammary nodes in addition to the whole breast or chest wall, depending on the type of surgery. Ongoing trials are testing the safety of omitting post-mastectomy breast and post-lumpectomy nodal irradiation (NCT01872975) as well as omitting axillary lymph node dissection (NCT01901094) in the setting of pCR. Additionally, evolving technologies such as minimal residual disease (MRD) monitoring in the blood during follow-up may allow early intervention with "second-line systemic adjuvant therapy" for patients with molecular relapse which might prevent impending clinical relapse.

OBJECTIVES/OBJECTIVE:To assess the risk of adverse diagnoses and laboratory abnormalities associated with a 300 mg or 150 mg daily dose of 3TC initiated by people living with HIV (PLWH) with an estimated glomerular filtration rate (eGFR) between ≥30 and ≤49 ml/min/1.73m2. DESIGN/METHODS:Longitudinal study based on electronic health records of 539 PLWH with eGFR between ≥30 and ≤49 ml/min/1.73m2 from the Observational Pharmaco-Epidemiology Research and Analysis (OPERA®) cohort. METHODS:Common unintended effects of 3TC were evaluated as composite outcomes. We estimated the incidence (univariate Poisson regression) and association between dose and incident composite outcomes (multivariate Poisson regression) among PLWH without the relevant diagnoses or laboratory abnormalities at 3TC initiation. RESULTS:PLWH initiating 150 mg 3TC had higher HIV RNA, lower eGFR, and more comorbidities than those initiating 300 mg 3TC. The prevalence of relevant diagnoses and laboratory abnormalities was similar in both groups. The most common lab abnormality was low hemoglobin. There was no statistically significant difference in incident adverse diagnoses/severe lab abnormalities with 300 mg versus 150 mg (incidence rate ratio [IRR]: 1.51; 95% confidence interval [CI]: 0.59, 3.92). However, a statistically significant association was observed when gastrointestinal symptoms/moderate lab abnormalities were included in the outcome (IRR: 3.07, 95% CI: 1.12, 8.40). CONCLUSIONS:Because 3TC is a well-tolerated drug with a wide therapeutic window, dose adjustment may be unnecessary among PLWH with eGFR between ≥30 and ≤49 ml/min/1.73m2. Clinical judgement is key when weighing the risks and benefits of 3TC dose adjustment for PLWH experiencing gastrointestinal symptoms or moderate lab abnormalities.

BACKGROUND:Guidelines recommend enteral nutrition (EN) within 48 h of admission to the medical intensive care unit (ICU) in appropriate patients. However, delayed EN is still common. OBJECTIVES/OBJECTIVE:This study sought to identify risk factors for delayed EN ordering in the ICU and to examine its association with patient outcomes. METHODS:This was a retrospective study from 2010-2018. Adult patients were included if they were admitted to the medical ICU for >48 h, were appropriate for EN, and had an order for EN placed within 30 d of admission. The primary outcome was ordering of EN, classified as early if ordered within 48 h of ICU admission and otherwise as delayed. Propensity score matching was used to examine the relation between delayed EN and ICU-free days, and outcomes such as length of ICU admission, length of hospitalization during 30 d of follow-up, and mortality. RESULTS:A total of 738 (79%) patients received early EN and 196 (21%) received delayed EN. The exposures most strongly associated with delayed EN were order placement by a Doctor of Medicine compared with a dietitian [adjusted OR (aOR): 2.58; 95% CI: 1.57, 4.24] and use of vasopressors within 48 h of ICU admission (aOR: 1.78; 95% CI: 1.22, 2.59). After propensity score matching to balance baseline characteristics, delayed EN ordering was significantly associated with fewer ICU-free days, longer ICU admissions, and longer hospitalizations, but not mortality, compared with early EN. CONCLUSIONS:Provider-level factors were associated with delayed ordering of EN which itself was associated with worse outcomes. Interventions directed at providers may increase timely EN in the ICU and improve outcomes.

Objective/UNASSIGNED:The widespread deployment of electronic health records (EHRs) has introduced new sources of error and inefficiencies to the process of ordering medications in the hospital setting. Existing work identifies orders that require pharmacy intervention by comparing them to a patient's medical records. In this work, we develop a machine learning model for identifying medication orders requiring intervention using only provider behavior and other contextual features that may reflect these new sources of inefficiencies. Materials and Methods/UNASSIGNED:Data on providers' actions in the EHR system and pharmacy orders were collected over a 2-week period in a major metropolitan hospital system. A classification model was then built to identify orders requiring pharmacist intervention. We tune the model to the context in which it would be deployed and evaluate global and local feature importance. Results/UNASSIGNED:The resultant model had an area under the receiver-operator characteristic curve of 0.91 and an area under the precision-recall curve of 0.44. Conclusions/UNASSIGNED:Providers' actions can serve as useful predictors in identifying medication orders that require pharmacy intervention. Careful model tuning for the clinical context in which the model is deployed can help to create an effective tool for improving health outcomes without using sensitive patient data.

Proton pump inhibitors (PPIs) are among the most commonly used medications in the world; however, these drugs carry the risk of patient harm, including acute and chronic kidney disease, Clostridium difficile infection, hypomagnesemia, and fractures. In the hospital setting, PPIs are overused for stress ulcer prophylaxis and gastrointestinal bleeding, and PPI use often continues after discharge. Numerous multifaceted interventions have demonstrated safe and effective reduction of PPI use in the inpatient setting. This narrative review and the resulting implementation guide summarize published interventions to reduce inappropriate PPI use and provide a strategy for quality improvement teams.