Enterococci, one of the most common causes of hospital-associated infections, are responsible for substantial morbidity and mortality. Enterococcus faecalis, the more common and virulent species, causes serious high-inoculum infections, namely infective endocarditis, that are associated with cardiac surgery and mortality rates that remained unchanged for the last 30 years. The best cures for these infections are observed with combination antibiotic therapy; however, optimal treatment has not been fully elucidated. It is the purpose of this review to highlight treatment options and their limitations, and provide direction for future investigative efforts to aid in the treatment of these severe infections. While ampicillin plus ceftriaxone has emerged as a preferred treatment option, mortality rates continue to be high, and from a safety standpoint, ceftriaxone, unlike other cephalosporins, promotes colonization with vancomycin resistant-enterococci due to high biliary concentrations. More research is needed to improve patient outcomes from this high-mortality disease.Keywords. Enterococcus faecalis; infective endocarditis; antimicrobials. , and ability to form biofilm at higher rates than E. faecium (87%-95% vs 16%-29%, respectively) [4,5], makes treatment of E. faecalis infections particularly challenging and may contribute to the unchanging mortality rates. Consequently, combination antimicrobial therapy is required for deep-seated E. faecalis infections, and with >50% of isolates expressing aminoglycoside resistance, treatment options are becoming limited [6]. It is the purpose of this review to highlight available treatment options and their limitations and to provide direction for investigation of future novel combination therapies, including ampicillin plus non-ceftriaxone β-lactams and daptomycin combination therapy, to further aid in the treatment of E. faecalis IE. METHODSStudies were identified by conducting PubMed and Embase searches using the following keywords in 1 or more combinations with "Enterococcus faecalis ": infective, endocarditis, bacteremia, bloodstream, infection, treatment, guideline, antibiotic, combination, synergy, resistant, biofilm, clinical, diagnosis, epidemiology, in vitro, in vivo, simulated endocardial vegetation, experimental, and β-lactamase. Manual searches of reference lists of relevant articles found from initial searches were also conducted. No limitation was placed on publication time period. Studies were selected based on authors' (M. B. and M. K. L.) judgment of relevance to topic. ORIGIN OF COMBINATION THERAPYFor serious E. faecalis infections, such as IE, bactericidal agents, often as combination therapy, are preferred [2]. β-Lactam antibiotics lack bactericidal activity against enterococci when used as monotherapy, making treatment of systemic infections

Matrix-assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF MS) decreases the time to organism identification and improves clinical and financial outcomes. The purpose of this study was to evaluate the impact of MALDI-TOF MS alone versus MALDI-TOF MS combined with real-time, pharmacist-driven, antimicrobial stewardship (AMS) intervention on patient outcomes. This single-center, pre-post, quasiexperimental study evaluated hospitalized patients with positive blood cultures identified via MALDI-TOF MS combined with prospective AMS intervention compared to a control cohort with MALDI-TOF MS identification without AMS intervention. AMS intervention included: real-time MALDI-TOF MS pharmacist notification and prospective AMS provider feedback. The primary outcome was the time to optimal therapy (TTOT). A total of 252 blood cultures, 126 in each group, were included in the final analysis. MALDI-TOF MS plus AMS intervention significantly reduced the overall TTOT (75.17 versus 43.06 h; P Ͻ 0.001), the Gram-positive contaminant TTOT (48.21 versus 11.75 h; P Ͻ 0.001), the Gramnegative infection (GNI) TTOT (71.83 versus 35.98 h; P Ͻ 0.001), and the overall hospital length of stay (LOS; 15.03 versus 9.02 days; P ϭ 0.021). The TTOT for Grampositive infection (GPI) was improved (64.04 versus 41.61 h; P ϭ 0.082). For GPI, the hospital LOS (14.64 versus 10.31 days; P ϭ 0.002) and length of antimicrobial therapy 24.30 versus 18.97 days; P ϭ 0.018) were reduced. For GNI, the time to microbiologic clearance (51.13 versus 34.51 h; P Ͻ 0.001), the hospital LOS (15.40 versus 7.90 days; P ϭ 0.027), and the intensive care unit LOS (5.55 versus 1.19 days; P ϭ 0.035) were reduced. To achieve optimal outcomes, rapid identification with MALDI-TOF MS combined with real-time AMS intervention is more impactful than MALDI-TOF MS alone.KEYWORDS MALDI-TOF MS, antimicrobial stewardship, rapid molecular diagnostics D espite advances in antimicrobial therapy, bloodstream infections (BSIs) remain a threat to hospitalized patients. A significant proportion of health care-associated infections result from multidrug-resistant organisms (MDROs). These infection rates continue to uptrend, posing a substantial public health risk by driving providers to utilize broad-spectrum antimicrobials and potentiating the cycle that creates MDROs

IntroductionApproximately 30% of all outpatient antimicrobials are inappropriately prescribed. Currently, antimicrobial prescribing patterns in emergency departments (ED) are not well described. Determining inappropriate antimicrobial prescribing patterns and opportunities for interventions by antimicrobial stewardship programs (ASP) are needed.MethodsA retrospective chart review was performed among a random sample of non-admitted, adult patients who received an antimicrobial prescription in the ED from January 1 to December 31, 2015. Appropriateness was measured using the Medication Appropriateness Index, and was based on provider adherence to local guidelines. Additional information collected included patient characteristics, initial diagnoses, and other chronic medication use.ResultsOf 1579 ED antibiotic prescriptions in 2015, we reviewed a total of 159 (10.1%) prescription records. The most frequently prescribed antimicrobial classes included penicillins (22.6%), macrolides (20.8%), cephalosporins (17.6%), and fluoroquinolones (17.0%). The most common indications for antibiotics were bronchitis or upper respiratory tract infection (URTI) (35.1%), followed by skin and soft tissue infection (SSTI) (25.0%), both of which were the most common reason for unnecessary prescribing (28.9% of bronchitis/URTIs, 25.6% of SSTIs). Of the antimicrobial prescriptions reviewed, 39% met criteria for inappropriateness. Among 78 prescriptions with a consensus on appropriate indications, 13.8% had inappropriate dosing, duration, or expense.ConclusionConsistent with national outpatient prescribing, inappropriate antibiotic prescribing in the ED occurred in 39% of cases with the highest rates observed among patients with bronchitis, URTI, and SSTI. Antimicrobial stewardship programs may benefit by focusing on initiatives for these conditions among ED patients. Moreover, creation of local guideline pocketbooks for these and other conditions may serve to improve prescribing practices and meet the Core Elements of Outpatient Stewardship recommended by the Centers for Disease Control and Prevention.

Objective Beta-lactam antibiotics are recommended as first-line for treatment of methicillin-sensitive Staphylococcus aureus (MSSA) bacteremia. The objective of this study was to compare effectiveness of anti-MSSA therapies among bacteremia patients exclusively exposed to 1 antimicrobial. Method This was a national retrospective cohort study of patients hospitalized in Veterans Affairs medical centers with MSSA bacteremia from January 1, 2002, to October 1, 2015. Patients were included if they were treated exclusively with nafcillin, oxacillin, cefazolin, piperacillin/tazobactam, or fluoroquinolones (moxifloxacin and levofloxacin). We assessed 30-day mortality, time to discharge, inpatient mortality, 30-day readmission, and 30-day S. aureus reinfection. Hazard ratios (HRs) and 95% confidence intervals (CI) were calculated using propensity-score (PS) matched Cox proportional hazards regression model. Results When comparing nafcillin/oxacillin (n = 105) with cefazolin (n = 107), 30-day mortality was similar between groups (PS matched n = 44; HR, 0.67; 95% CI, 0.11–4.00), as were rates of the other outcomes assessed. As clinical outcomes did not vary between nafcillin/oxacillin and cefazolin, they were combined for comparison with piperacillin/tazobactam (n = 113) and fluoroquinolones (n = 103). Mortality in the 30 days after culture was significantly lower in the nafcillin/oxacillin/cefazolin group compared with piperacillin/tazobactam (PS matched n = 48; HR, 0.10; 95% CI, 0.01–0.78), and similar when compared with fluoroquinolones (PS matched n = 32; HR, 1.33; 95% CI, 0.30–5.96). Conclusions In hospitalized patients with MSSA bacteremia, no difference in mortality was observed between nafcillin/oxacillin and cefazolin or fluoroquinolones. However, higher mortality was observed with piperacillin/tazobactam as compared with nafcillin/oxacillin/cefazolin, suggesting it may not be as effective as a monotherapy in MSSA bacteremia.

C andida auris is an emerging, multidrug-resistant, healthcare-associated fungal pathogen that was first reported in Japan in 2009 and has now been isolated on 6 continents (1-9). C. auris has been identified as the causative pathogen in various invasive fungal infections, including bloodstream infections (2,4), and is associated with outbreaks across healthcare settings (6,10). Risk factors for C. auris infection are similar to other Candida infections including prolonged hospitalization, abdominal surgery, diabetes mellitus, intensive care unit (ICU) admission, use of central venous and urinary catheters, immunocompromising conditions, chronic kidney disease, and exposure to broad-spectrum antibiotic and antifungal agents (10-13). Investigations in the Chicago, Illinois, USA, area have found a high prevalence of C. auris colonization at ventilator-capable skilled nursing facilities (14) and have shown higher rates of C. auris colonization among patients who are mechanically ventilated, have a gastrostomy tube, or have a urinary catheter (15). Reported mortality rates attributable to invasive C. auris infection range from 30% to 59% globally (13,16) and from 22% to 57% in the United States (8,10,17). C. auris isolates are often resistant to fluconazole and have variable susceptibility to other antifungal agents (13,16). The Centers for Disease Control and Prevention (CDC) currently recommends echinocandins as empiric therapy for suspected or confirmed C. auris infections (18). However, recent reports have indicated reduced susceptibilities to echinocandins and suggest that resistance might be inducible under antifungal pressure (8,16). Previous reports of C. auris infections and outbreaks have largely focused on epidemiologic information, and data on treatment strategies and clinical outcomes are limited (6,8,10,16-21). We report microbiologic data for C. auris isolates from a multisite health system in Illinois and an assessment of clinical outcomes for patients treated for C. auris infections. Methods This study is a retrospective cohort analysis of patients at 8 hospitals within a single health system located in the Chicago metropolitan area. We included all patients >18 years old who had >1 positive culture for C. auris from any anatomic site during January 1,

Fluoroquinolones (FQs) are often preferred as oral step-down therapy for bloodstream infections (BSIs) due to favorable pharmacokinetic parameters; however, they are also associated with serious adverse events. The objective of this study was to compare clinical outcomes for patients who received an oral FQ versus an oral beta-lactam (BL) as step-down therapy for uncomplicated streptococcal BSIs. This multi-center, retrospective cohort study analyzed adult patients who completed therapy with an oral FQ or BL with at least one blood culture positive for a Streptococcus species from January 1, 2014 to June 30, 2019. The primary outcome was clinical success, defined as lack of all-cause mortality, recurrent BSI with the same organism, and infection-related readmission at 90 days. A multivariable logistic regression model for predictors of clinical failure was conducted. A total of 220 patients were included, with 87 (40%) receiving a FQ and 133 (60%) receiving a BL. Step-down therapy with an oral BL was non-inferior to an oral FQ (93.2% vs. 92.0%; mean difference 1.2%, 90% CI -5.2 to 7.8). No differences were seen in 90-day mortality, 90-day recurrent BSI, 90-day infection-related readmission, or 90-day incidence of C. difficile-associated diarrhea. Predictors of clinical failure included: oral step-down transition before day three (OR = 5.18, 95% CI 1.21, 22.16) and low dose oral-step down therapy (OR = 2.74, 95% CI 0.95, 7.90). Our results suggest that oral step-down therapy for uncomplicated streptococcal BSI with a BL is non-inferior to a FQ.

Acinetobacter baumannii is recognized as an urgent public health threat by the Centers for Disease Control and Prevention (CDC). Current treatment options are scarce, particularly against carbapenem-resistant Acinetobacter baumannii (CRAB). We simulated the impact of minocycline standard (200mg load+100mg Q12h) and high-dose (700mg load+ 350mg Q12h), polymyxin B (2.5mg/kg Q12h), sulbactam (1g Q6h and 9g/24h as continuous infusion) and meropenem (intermittent 1 or 2g Q8h and 6g/24h as continuous infusion) alone or in combination against CRAB and non-CRAB isolates by simulating human therapeutic dosing regimens in a 72-hour, in vitro pharmacodynamic model (IVPD). There were no monotherapy regimens that demonstrated bactericidal activity against the tested non-CRAB and CRAB. Resistance development was common in monotherapy regimens. Against the CRAB isolate, the triple combination of high-dose minocycline (fAUC/MIC 21.21), polymyxin B (fAUC/MIC 15.63), and continuous infusion sulbactam (67% T>MIC) was the most consistently active regimen. Against non-CRAB, the triple therapy regimen of high-dose minocycline (fAUC/MIC 84.84) with continuous infusion meropenem (100%T>MIC) and continuous infusion sulbactam (83%T>MIC), as well as the double therapy of high-dose minocycline (AUC/MIC 84.84) with continuous infusion meropenem (100%T>MIC) resulted persistently bactericidal activity. In conclusion, triple therapy with high dose minocycline, continuous infusion sulbactam, and polymyxin B produced the most significant kill against the carbapenem-resistant Acinetobacter baumannii, with no regrowth and minimal resistance development.

BackgroundThough recurrent Clostridium difficile infection (CDI) is common and poses a major clinical concern, data are lacking regarding mortality among patients who survive their initial CDI and have subsequent recurrences. Risk factors for mortality in patients with recurrent CDI are largely unknown.MethodsVeterans Affairs patients with a first CDI (stool sample with positive C. difficile toxin(s) and ≥2 days CDI treatment) were included (2010–2014). Subsequent recurrences were defined as additional CDI episodes ≥14 days after the stool test date and within 30 days of the end of treatment. A matched (1:4) case–control analysis was conducted using multivariable conditional logistic regression to identify predictors of all-cause mortality within 30 days of the first recurrence.ResultsCrude 30-day all-cause mortality rates were 10.6% for the initial CDI episode, 8.3% for the first recurrence, 4.2% for the second recurrence, and 5.9% for the third recurrence. Among 110 cases and 440 controls, 6 predictors of mortality were identified: use of proton pump inhibitors (PPIs; odds ratio [OR], 3.86; 95% confidence interval [CI], 2.14–6.96), any antibiotic (OR, 3.33; 95% CI, 1.79–6.17), respiratory failure (OR, 8.26; 95% CI, 1.71–39.92), congitive dysfunction (OR, 2.41; 95% CI, 1.02–5.72), nutrition deficiency (OR, 2.91; 95% CI, 1.37–6.21), and age (OR, 1.04; 95% CI, 1.01–1.07).ConclusionsIn our national cohort of Veterans, crude mortality decreased by 44% from the initial episode to the third recurrence. Treatment with antibiotics, use of PPIs, and underlying comorbidities were important predictors of mortality in recurrent CDI. Our study assists health care providers in identifying patients at high risk of death after CDI recurrence.