Risk Of Clinical Failure Research Articles

Wild-Type AmpC Beta-Lactamase-Producing Enterobacterales Are a Risk Factor for Empirical Treatment Failure in Patients with Bloodstream Infection.

Introduction: Beta-lactamases are frequently prescribed for Gram-negative bloodstream infections (BSIs). However, chromosomally encoded AmpC-producing Enterobacterales (AE) could overproduce beta-lactamases when exposed to third-generation cephalosporins (3GCs), with a risk of clinical failure. There are few available in vivo data on the subject. Our goal was to assess the potential role of AE as a predictive factor for clinical failure in patients with BSIs. Materials and Methods: We retrospectively analyzed patients admitted to Cannes hospital between 2021 and 2022 for BSIs due to Enterobacterales. Patient demographics, comorbidities, and main clinical and laboratory parameters during hospitalization were collected. The risk factors for clinical instability after 48 h or death, as well as for ineffective initial empirical therapy, were assessed using univariate and multivariate analyses. Results: From January 2021 to December 2022, 101 subjects were included (mean age 79 years, 60% men, 97% with comorbidities, 17% with healthcare-associated infection, 13% with septic shock, 82% with qPitt severity score < 2, 58% with urinary tract infection, and 18% with AE). Septic shock [adjusted odds ratio (ORadj) = 5.30, 95% confidence interval (CI): 1.47-22.19, p = 0.014] and ineffective initial empirical therapy [ORadj 5.54, 95% CI: 1.95-17.01, p = 0.002] were independent predictive factors for clinical instability or death. Extended-spectrum beta-lactamases [ORadj 9.40, 95% CI: 1.70-62.14, p = 0.012], AE group [ORadj 5.89, 95% CI: 1.70-21.40, p = 0.006], and clinical instability or death [ORadj 4.71, 95% CI: 1.44-17.08, p = 0.012] were independently associated with ineffective empirical therapy. Conclusions: Infection with AE was associated with treatment failure. Empirical therapy may result in failure if restricted to 3GC.

Clinical outcome of wild-type AmpC-producing Enterobacterales infection in critically ill patients treated with β-lactams: a prospective multicenter study

Backgroundβ-lactams are the main antibiotics used against wild-type AmpC-producing Enterobacterales (wtAE). However, they may fail or select AmpC-overproducing mutants. Our aim was to assess factors associated with clinical failure of β-lactams in the treatment of wtAE infection.MethodsFrom September 2017 to December 2020, we prospectively included all consecutive patients treated by definitive β-lactams therapy for wtAE infection in four university ICUs. Clinical failure was defined as inadequate response to antimicrobial therapy leading to death or to the switch for a broader-spectrum antibiotic.Results177 patients were included and 29.4% progressed to clinical failure. E. cloacae was the most prevalent species (42.4%) and ventilator-associated pneumonia (VAP) was the most frequent wtAE infection (69.5%). Cefepime and cefotaxime were used as definitive antibiotic treatment in 42.9% and 27.7% of patients, respectively. Occurrence of AmpC-overproduction was documented in 5.6% of patients and was associated with clinical failure (p = 0.004). In multivariate analysis, VAP (p < 0.001, OR 11.58 [95% CI 3.11–43.02] and K. aerogenes (p = 0.030, OR 3.76 [95% CI 1.13–12.46]) were independently associated with clinical failure. Conversely, cefotaxime as definitive treatment was found inversely associated with the risk of clinical failure (p = 0.022, OR 0.25 [95% CI 0.08–0.82]). After inverse probability weighting, cefotaxime showed a 20% risk reduction of clinical failure (95% CI 5–35%, p = 0.007) whatever the location of infection, the SOFA score on the day of wtAE infection, or the bacterial species.ConclusionsClinical failure in the treatment of wtAE infections is associated with the infection site and the causal microorganism. Additionally, cefotaxime use is probably protective against clinical failure in wtAE infection.

The association between empiric antimicrobial therapy and the risk of clinical failure in critically ill patients with aspiration pneumonia.

Aspiration pneumonia is a clinically important infectious process that can result in increased morbidity and mortality. Empiric antimicrobial therapy with activity against anaerobes has been a standard practice based on previous studies, which isolated anaerobes from respiratory cultures. Recent studies have failed to identify anaerobes as causative pathogens, however, these studies did not assess patient outcomes based on the presence or absence of anaerobic coverage. This retrospective cohort study evaluated patients at least 18 years of age requiring mechanical ventilation diagnosed with aspiration pneumonia between 1 October 2020 and 31 July 2021. The primary outcome was the incidence of clinical failure. Secondary outcomes included the time to clinical failure, the incidence of Clostridioides difficile infections and development of multidrug-resistant infections, as well as time on mechanical ventilation and intensive care unit length of stay. A total of 141 patients were included with 83 patients initially receiving anaerobic coverage and 58 patients treated without anaerobic coverage. There was no difference in the incidence of clinical failure between cohorts (18.1% vs. 22.4%; p= 0.41). There was a statistically significant difference in anaerobic escalations with more escalations in the cohort without anaerobic coverage (0% vs. 20.7%; p< 0.0001). Patients initially treated with drugs with anaerobic activity had a higher incidence of multidrug resistant infections on current admission (7.2% vs. 0%; p= 0.04) and a longer length of intensive care unit stay. In critically ill adults with aspiration pneumonia, our study found no difference in clinical failure based on the presence or absence of empiric anaerobic coverage adding to evolving literature suggesting that anaerobic coverage is not routinely warranted in this patient population. Interpretation of the results needs to consider, however, that the retrospective design led to the inclusion of sicker patients in the anaerobic cohort. The frequency of empiric anaerobic coverage demonstrates the need for a prospective randomized control trial to confirm these findings.

External Review and Validation of a Spinal Epidural Abscess Predictive Score for Clinical Failure

Spinal epidural abscess (SEA) is a rare but serious pathology that may result in delayed neurologic injury despite treatment with antibiotic therapy or surgery. Given this, the development of predictive scores for risk stratification has value in clinical decision making; however, external validation is necessary to understand their generalizability and reliability. A retrospective review was conducted of all patients presenting with SEA at a single institution. Patients were reviewed and graded according to the proposed SEA predictive score by Baum etal. Clinical failure was defined as documented laboratory or radiographic progression requiring surgical intervention, increased deformity requiring surgical intervention, or repeat surgical intervention if prior surgical intervention was undertaken as the initial treatment strategy. Brier score and receiver operating characteristic were used to calculate reliability. There were 224 patients presenting with primary spinal infections with associated SEA. Of these, 209 patients had no history of intravenous drug abuse. Clinical failure was demonstrated in 52 of 209 patients (24.9%). Antibiotic treatment alone compared with antibiotic therapy and surgical treatment on initial presentation was found to have a significantly greater chance of clinical failure (odds ratio= 3.0930, P= 0.01). The proposed epidural abscess prediction score did not correlate with clinical outcomes with a Brier score of 0.229 and receiver operating characteristic area under the curve of 0.5944. The proposed risk stratification scale for patients was not correlated with risk of clinical failure. Additionally, patients treated with antibiotics and surgical intervention on initial presentation had a significantly lower clinical failure rate.

Mid-term prognosis of the stromal vascular fraction for knee osteoarthritis: a minimum 5-year follow-up study

BackgroundThe short-term safety and efficacy of stromal vascular fraction (SVF) in treating knee osteoarthritis (KOA) have been extensively studied but the mid-term and long-term prognoses remain unknown.Methods126 KOA patients were recruited and randomly assigned to SVF group and hyaluronic acid (HA) group (control group). The scores of visual analogue scale (VAS) and the Western Ontario and McMaster University Osteoarthritis Index (WOMAC) were assessed and compared between the two groups 1, 2, 3, and 5 years after treatment. The endpoint was defined as surgeries related to KOA or clinical scores exceeding the patient acceptable symptom state (PASS).ResultsThe VAS and WOMAC scores in the SVF group were significantly better than those in the HA group during the 5-year follow-up after treatment. The average responsive time to SVF treatment (61.52 months) was significantly longer than HA treatment (30.37 months). The adjusted Cox proportional hazards model showed that bone marrow lesion (BML) severity, body mass index (BMI) and treatment were independent risk factors and that the use of SVF reduced the risk of clinical failure by 2.602 times. The cartilage volume was reduced in both the SVF and control groups at 5 years but reduced less in the SVF group.ConclusionsUp to 5 years after SVF treatment, acceptable clinical state was present for approximately 60% of patients. BML severity and BMI were independent predictors of the prognosis.Trial Registry: This study was retrospectively registered at Chinses Clinical Trial Registry with identifier ChiCTR2100052818 and was approved by ethics committee of the First Affiliated Hospital of Zhejiang Chinese Medical University, number 2013-X-063.

1259. Carbapenems Versus Non-carbapenem Beta-Lactams for the Treatment of Ceftriaxone-Susceptible and Piperacillin-Tazobactam-Nonsusceptible Enterobacterales Isolates

Abstract Background Ceftriaxone-susceptible (CRO-S) and piperacillin-tazobactam-non susceptible (TZP-NS) Enterobacterales isolates have become a frequently isolated phenotype emerging in practice. The genotypic profile is still not clearly elucidated, although prior genotypic sequencing data of these isolates with this phenotypic profile suggests that they are not extended-spectrum beta-lactamase (ESBL) producers. Due to the unfamiliarity with this phenotype and the potential for overuse of broad-spectrum antibiotics, we investigated the clinical outcomes of CRO-S/TZP-NS isolates with carbapenem versus non-carbapenem beta-lactam (NCBL) therapy. Methods This was a retrospective chart review of patients with a diagnosed infection caused by a CRO-S/TZP-NS Enterobacterales isolate admitted to any of the three NYU hospitals: Long Island, Tisch, or Brooklyn campuses, treated with a beta-lactam (BL) antibiotic from October 2015 to October 2020. The primary outcome was treatment failure defined as an escalation of antibiotics due to clinical worsening, 30-day all-cause mortality, or relapse of infection with the same genus and species. Patients who received ≥ 72 consecutive hours of BL antibiotics were considered to be on definitive therapy. Results A total of 111 patients were included in this study, 9 in the carbapenem group and 102 in the NCBL group. There was no statistically significant difference in the clinical failure rate between the two groups (0% vs 10.8% respectively, P=0.56). A univariate analysis assessed the association of clinical failure with TZP, CRO, cefpodoxime, cefepime, and 1st-3rd generation cephalosporins grouped. There were no statistically significant increases in 30-day treatment failure in any of the individual categories. Conclusion There were no statistically significant differences in 30-day failure with the use of carbapenem vs NCBL antibiotics. No individual BLs or classes were associated with an increased risk of clinical failure. This study suggests that there is a role for NCBL antibiotics for Enterobacterales isolates with this phenotypic presentation and supports prior data that they are less likely to be ESBL producers. Prospective studies are warranted to confirm these findings. Disclosures All Authors: No reported disclosures

Effectiveness of oseltamivir treatment on clinical failure in hospitalized patients with lower respiratory tract infection

BackgroundInfluenza is associated with excess morbidity and mortality of individuals each year. Few therapies exist for treatment of influenza infection, and each require initiation as early as possible in the course of infection, making efficacy difficult to estimate in the hospitalized patient with lower respiratory tract infection. Using causal machine learning methods, we re-analyze data from a randomized trial of oseltamivir versus standard of care aimed at reducing clinical failure in hospitalized patients with lower respiratory tract infection during the influenza season.MethodsThis was a secondary analysis of the Rapid Empiric Treatment with Oseltamivir Study (RETOS). Conditional average treatment effects (CATE) and 95% confidence intervals were computed from causal forest including 85 clinical and demographic variables. RETOS was a multicenter, randomized, unblinded, trial of adult patients hospitalized with lower respiratory tract infections in Kentucky from 2009 through 2012. Adult hospitalized patients with lower respiratory tract infection were randomized to standard of care or standard of care plus oseltamivir as early as possible after hospital admission but within 24 h of enrollment. After randomization, oseltamivir was initiated in the treatment arm per package insert. The primary outcome was clinical failure, a composite measure including failure to reach clinical improvement within 7 days, transfer to intensive care 24 h after admission, or rehospitalization or death within 30 days.ResultsA total of 691 hospitalized patients with lower respiratory tract infections were included in the study. The only subgroup of patients with a statistically significant CATE was those with laboratory-confirmed influenza infection with a 26% lower risk of clinical failure when treated with oseltamivir (95% CI 3.2–48.0%).ConclusionsThis study suggests that addition of oseltamivir to standard of care may decrease clinical failure in hospitalized patients with influenza-associated lower respiratory tract infection versus standard of care alone. These results are supportive of current recommendations to initiate antiviral treatment in hospitalized patients with confirmed or suspected influenza as soon as possible after admission.Trial registration Original trial: Clinical Trials.Gov; Rapid Empiric Treatment With Oseltamivir Study (RETOS) (RETOS); ClinicalTrials.gov Identifier: NCT01248715 https://clinicaltrials.gov/ct2/show/NCT01248715

Clinical Failure and Emergence of Resistance during Third Generation Cephalosporin Therapy for Enterobacter spp. Infection: Is the Risk Overestimated? A Prospective Multicentric Study

Background: Clinical and microbiological guidelines recommend treating infections caused by Enterobacter spp. with cefepime or carbapenems. The main objective of this study was to assess the risk of clinical failure with third generation cephalosporin (3GC) therapy compared to other β-lactams for infections caused by Enterobacter spp. Our secondary objective was to evaluate the risk of emergence of resistance during therapy. Methods: We conducted a prospective observational study in seven French hospitals over an 18-month period including all patients with a pulmonary and/or bloodstream infection due to Enterobacter spp. susceptible to 3GC. Results: Seventy-four patients were included in our study. Among them, 26 (35%) received a 3GC as a first-line treatment, and clinical improvements were observed for 13/21 (62%) of them. Four (5%) cases of emergence of 3GC resistance were observed during therapy including one in the 3GC group. 3GC therapy can be safely used as first-line therapy especially for non-severe patients suffering from pulmonary or bloodstream infections due to Enterobacter spp. Conclusions: Emergence of 3GC resistance remains a rare event, and there is a lack of evidence of the benefit of last-line antibiotics therapies.

Antipseudomonal β-Lactams Resistance in Iran.

Over the last years, the mortality rate of Pseudomonas aeruginosa, which is one of the major reasons for severe infections, has been significantly increasing. This bacterium is highly resistant to many antibiotics, especially carbapenems, thanks to its complicated mechanism by which it can acquire exogenous genes. The purpose of this research is to have a review of empirical studies surveying the P. aeruginosa resistance to beta-lactams in Iran in order to investigate the most reliable methods by which the incidence of P. aeruginosa infections can be decreased and controlled. We performed a systematic review of all articles published from 2008 until 2018. Studies which did not address P. aeruginosa resistance to beta-lactams were excluded from the analysis. Studies with less than 10 cases were also excluded. Studies with more than ten cases, which did not have repetitive information, were taken into account for the final selection; 133 out of 893 articles were chosen. The resistance rate of P. aeruginosa among the articles was as follows: more than 72% of studies revealed >50% level of resistance to cefepime, followed by aztreonam (53.2%), ceftazidime (61%), piperacillin/tazobactam (54.5%), meropenem (48.3%), and imipenem (42.4%). The selection of empiric antipseudomonal antibiotics is absolutely uncertain and hazardous, and the risk of clinical failure may be more among cephalosporins and piperacillin-tazobactam as well as aztreonam. The results of this study illustrate that the methods enabling clinics to identify the bacterium resistance pattern and its genetic basis and to have the opportunity of empiric therapies through access to updated local data of antimicrobial susceptibility pattern are the most effective methods. However, the widespread usage of these approaches undoubtedly needs reliable molecular and nucleic acid-based devices, which are both affordable and available.

Initial combination therapy of ambrisentan and tadalafil in connective tissue disease-associated pulmonary arterial hypertension (CTD-PAH) in the modified intention-to-treat population of the AMBITION study: post hoc analysis

ObjectivesTo evaluate initial combination therapy with ambrisentan plus tadalafil (COMB) compared with monotherapy of either agent (MONO), and the utility of baseline characteristics and risk stratification in predicting outcomes, in...

Effectiveness of Shorter Versus Longer Durations of Therapy for Common Inpatient Infections Associated With Bacteremia: A Multicenter, Propensity-Weighted Cohort Study.

National guidelines for pneumonia (PNA), urinary tract infection (UTI), and acute bacterial skin and skin structure infection (ABSSSI) do not address treatment duration for infections associated with bacteremia. We evaluated clinical outcomes of patients receiving shorter (5-9 days) versus longer (10-15 days) duration of antibiotics. This was a multicenter retrospective cohort study of inpatients with uncomplicated PNA, UTI, or ABSSSI and associated bacteremia. The primary outcome was clinical failure, a composite of rehospitalization, reinitiation of antibiotics, or all-cause mortality within 30 days of antibiotic completion. Secondary outcomes included individual components of the primary outcome, Clostridioides difficile infection, and antibiotic-related adverse effects necessitating change in therapy. A propensity score-weighted logistic regression model was used to mitigate potential bias associated with nonrandom assignment of treatment duration. Of 408 patients included, 123 received a shorter treatment duration (median 8 days) and 285 received a longer duration (median 13 days). In the propensity-weighted analysis, the probability of the primary outcome was 13.5% in the shorter group and 11.1% in the longer group (average treatment effect, 2.4%; odds ratio [OR], 1.25; 95% confidence interval [CI], .65-2.40; P = .505). However, shorter courses were associated with higher probability of restarting antibiotics (OR, 1.62; 95% CI, 1.01-2.61; P = .046) and C. difficile infection (OR, 4.01; 95% CI, 2.21-7.59; P < .0001). Shorter courses of antibiotic treatment for PNA, UTI, and ABSSSI with bacteremia were not associated with increased overall risk of clinical failure; however, prospective studies are needed to further evaluate the effectiveness of shorter treatment durations.

Safety and Efficacy of Peroral Endoscopic Myotomy for the Treatment of Achalasia in Children: A Large Multi-Center Study

Background: Peroral endoscopic myotomy (POEM) has showed excellent results for the treatment of achalasia in adults, but studies of POEM for children are limited. In this study, we comprehensively analyzed outcomes of POEM in children and compared with those in adults in a large multi-center study. Methods: Between August 2010 and December 2015, records of consecutive patients with achalasia who underwent POEM at three tertiary centers were reviewed. A total of 130 children were included in this study. The primary outcomes of perioperative outcomes and clinical follow-up data were analyzed. Findings: One child (0*8%) experienced technical failure. Five children (3*8%) had major adverse events, including one with pneumothorax requiring drainage, two with delayed mucosa barrier failure, one with readmission, and one with vital sign instability. Both post-POEM Eckardt score and median LES pressure were significantly lower than their pre-POEM reference values in children (0*7 vs 7*4; 7*0 vs 27*1 mmHg; both P 0*05). Kaplan-Meier analysis showed that the risk of clinical failure was lower in children than adults (log-rank test, hazard ratio=0*37, 95% confidence interval 0*15-0*91, P=0*023). Interpretation: POEM can be safely and effectively performed in children with achalasia. In addition, it produces a better clinical response during long-term follow-up compared with that in adults. Funding: This study was supported by grants from the National Natural Science Foundation of China (81873552, 81470811, 81570595, and 81670483), Major Project of Shanghai Municipal Science and Technology Committee (18ZR1406700, 16411950400, 16DZ2280900), Chen Guang Program of Shanghai Municipal Education Commission (15CG04), and Outstanding Young Doctor Training Project of Shanghai Municipal Commission of Health and Family Planning (2017YQ026), and the Project of Shanghai Municipal Commission of Health and Family Planning (SHDC12016203). Declaration of Interest: All authors have none to declare. Ethical Approval: This retrospective study was approved by the local ethics committee. Written informed consent was obtained before POEM from patients or their caretakers if patients were <16 years of age.

Correction: The effect of prior treatment on clinical outcomes in patients with achalasia undergoing peroral endoscopic myotomy.

Background Peroral endoscopic myotomy (POEM) is a treatment option for patients with previous surgical or endoscopic treatment. We aimed to evaluate the influence of prior treatment on perioperative and follow-up outcomes in patients undergoing POEM. Methods From August 2010 to December 2014, a total of 1384 patients with achalasia underwent POEM at our center. We retrospectively reviewed 849 patients who completed follow-up. Patients with an Eckardt score ≥ 4 after POEM were considered to have a clinical failure. We compared variables between patients with and without prior treatment. We analyzed risk factors for perioperative major adverse events, and clinical reflux and failure during follow-up. Results 245 patients (28.9 %) had undergone prior treatment, and 34 patients (4.0 %) experienced a major adverse event associated with the POEM procedure. During a median follow-up of 23 months (range 1 – 71), clinical reflux occurred in 203 patients (23.9 %) and clinical failure was recorded for 94 patients (11.1 %). Patients with prior treatment had a longer procedure duration (P = 0.001) and longer hospital stay after POEM (P = 0.001). Prior treatment was not an independent risk factor for major adverse events or clinical reflux (odds ratio [OR] 1.19, P = 0.65; OR 1.26, P = 0.19; logistic regression), but it did increase the rate of clinical failure during follow-up (hazard ratio 1.90, P = 0.002; Cox regression). Conclusions POEM was performed safely with a low rate of major adverse events in patients with achalasia who had undergone prior surgical or endoscopic treatment. However, prior treatment increased the risk of clinical failure after POEM.

Initial combination therapy with ambrisentan + tadalafil on pulmonary arterial hypertension‒related hospitalization in the AMBITION trial.

In the randomized, double-blind, event-driven AMBITION study, initial combination therapy with ambrisentan and tadalafil was associated with a 50% reduction in risk of clinical failure (first occurrence of all-cause death, hospitalization for worsening pulmonary arterial hypertension [PAH], disease progression, or unsatisfactory long-term clinical response) vs pooled monotherapy. These results were primarily driven by a reduction in PAH-related hospitalization in the combination therapy group, although a significant effect was not observed in a post-hoc analysis of all-cause hospitalization. The effect of initial combination therapy with ambrisentan and tadalafil in AMBITION was further explored to study PAH-related hospitalization, which was not reported in the primary publication. Initial combination therapy was associated with a 63% reduction in risk of PAH-related hospitalization when compared with pooled monotherapy (hazard ratio [HR] 0.372, 95% confidence interval [CI] 0.217 to 0.639,p = 0.0002). For every 9 patients treated with combination therapy vs monotherapy, 1 PAH-related hospitalization could be prevented over a 1-year period. Serious adverse events leading to hospitalization, not necessarily PAH-related, occurred in 87 of 253 (34%) and 89 of 247 (36%) of patients on combination therapy and pooled monotherapy, respectively (post-hoc summary). Initial combination therapy with ambrisentan and tadalafil was found to reduce the risk of PAH-related hospitalization by 63% compared with pooled monotherapy.

Duration of interventricular septal shift toward the left ventricle is associated with poor clinical outcome in precapillary pulmonary hypertension: A cardiac magnetic resonance study

BackgroundRight ventricular pressure overload results in interventricular septal shift toward the left ventricle in patients with precapillary pulmonary hypertension (PH). We aimed to investigate the predictive role of the duration of septal curvature configuration during the cardiac cycle, as expressed by the novel marker curvature duration index (CDi) in precapillary PH. MethodsThis was a prospective study. All patients underwent cardiac magnetic resonance (CMR). CDi was defined by the number of CMR frames in which septal curvature configuration toward left ventricle is observed *100/total number of frames per cardiac cycle. Time from enrollment to first clinical failure event (death, hospitalization due to PH, and disease progression) was recorded. ResultsThe study included 36 patients with precapillary PH. During a median follow-up of 20 months (IQR 4-37 months), 14 clinical failure events were observed. Survival ROC analysis showed that the optimal cutoff value of CDi, which predicted clinical failure, was 67%. Kaplan–Meier survival analysis showed that CDi≥67% was associated with a 9.4-fold increase in the risk for clinical failure. Addition of CDi to baseline models including six-minute walk test distance (c-statistic = 0.65 vs. c-statistic = 0.79), NT-proBNP (c-statistic = 0.72 vs. c-statistic = 0.83), and WHO functional class (c-statistic = 0.76 vs. c-statistic = 0.81) improved risk stratification. ConclusionVentricular septal shift toward the left ventricle lasting for more than the two thirds of the cardiac cycle is associated with worse prognosis in precapillary PH.

Ambrisentan ± tadalafil in WHO functional class II/III pulmonary arterial hypertension: a guide to its use in the EU

Ambrisentan [Volibris® (EU), Letairis® (USA)], an endothelin-1 receptor antagonist, is effective in treating WHO functional class (FC) II/III pulmonary arterial hypertension (PAH) when used as monotherapy or in combination with tadalafil (a phosphodiesterase type-5 inhibitor). In patients with idiopathic PAH or PAH associated with connective tissue diseases, ambrisentan monotherapy provided sustained clinical benefits, including improvements in exercise capacity. Clinical benefits, including a lower risk of clinical failure, were greater with initial combination treatment with ambrisentan + tadalafil than with initial monotherapy with either ambrisentan or tadalafil in patients with PAH, including those in various patient subgroups. Ambrisentan has an acceptable tolerability and safety profile with or without concomitant tadalafil. Based on the results of clinical trials, current guidelines recommend ambrisentan as initial mono- or combination treatment in patients with non-vasoreactive WHO FC class II/III PAH.

Poor Clinical Outcomes Associated with Community-Onset Extended-Spectrum Cephalosporin-Resistant Enterobacteriaceae Urinary Tract Infections

BackgroundUrinary tract infections (UTIs) are the most common bacterial infection among adults in the community. Recent data suggest an increase in bacterial resistance to first line antibiotics used for UTI, though the impact on clinical outcomes is unclear. The objective of our study was to determine clinical outcomes associated with community-onset extended-spectrum cephalosporin-resistant (ESC-R) Enterobacteriaceae (EB) UTI.MethodsA retrospective cohort study was conducted in a large health system from 2010 to 2013. All patients presenting to an emergency department or outpatient clinic with UTI due to EB were included. Exposed subjects were those with an EB demonstrating resistance to an ESC (ceftriaxone or ceftazidime). Unexposed subjects were those with ESC-susceptible EB UTIs and were matched to cases 1:1 based on study year. Multivariable logistic regression analyses were performed to evaluate the association between ESC-R EB UTI and 1) clinical failure (defined as ongoing symptoms, repeat positive culture, or need for additional antibiotics within 7 days); 2) inappropriate initial antibiotic therapy (IIAT) (defined as failure to receive an antibiotic to which the organism was susceptible within 48 hours of presentation).ResultsA total of 302 patients with community-onset EB UTI were included. On multivariable analyses, a UTI with an ESC-R EB was significantly associated with clinical failure (odds ratio [OR] 5.12, 95% confidence interval [CI] 2.79–9.39, P < 0.01). Other variables independently associated with clinical failure included presence of pyelonephritis at the time of UTI diagnosis (OR 2.15, 95% CI 1.14–4.03, p 0.02) and infection with Citrobacter species (OR 29.56, 95% CI 4.46–195.91, P < 0.01). ESC-R EB UTI was also associated with IIAT on multivariable analysis (OR 3.73, 95% CI 2.25–6.21, P < 0.01).ConclusionCommunity-onset UTI due to an ESC-R EB organism is associated with a significantly increased risk of clinical failure, which may be due in part to the use of inappropriate initial antibiotic therapy. Further studies are needed to determine which patients in the community are at high risk for drug-resistant infection to help inform prompt urine culture ordering and appropriate antibiotic prescribing for ESC-R EB.Disclosures All authors: No reported disclosures.

Comparison of Outcomes in Outpatient Parenteral Antimicrobial Therapy (OPAT) Patients Receiving Vancomycin vs. Non-Vancomycin Anti-MRSA Therapy

BackgroundThis evaluation set out to determine whether vancomycin therapy was associated with higher rates of clinical failure compared with non-vancomycin anti-methicillin-resistant Staphylococcus aureus therapy (NVAMT) in outpatient parenteral antimicrobial therapy (OPAT).MethodsThis was a retrospective, single center cohort study including patients who received ≥7 days of OPAT with vancomycin, ceftaroline, or daptomycin from January 1, 2009 through March 31, 2016 at the VA Saint Louis Healthcare System. The primary outcome was clinical failure, defined as a composite of acute kidney injury (AKI), creatinine phosphokinase elevations ≥ 500 units/L, adverse drug events necessitating a change in therapy, readmission due to recurrence of infection, or reinitiation of antibiotics after discontinuation. Secondary outcomes were the individual components of the composite primary outcome. Multivariate logistic regression was used to evaluate independent risk factors for clinical failure. Factors evaluated for inclusion in the multivariate model were age >65 at initiation, creatinine clearance >50 mL/minute, length of therapy >28 days, concomitant antibiotic therapy, comorbid disease states, and vancomycin therapy.ResultsA total of 125 patients were included in the analysis – 72 receiving vancomycin and 53 receiving NVAMT. Baseline characteristics between groups were similar, except patients in the NVAMT group had a greater mean serum creatinine and a higher rate of CKD at baseline; 1.53 vs 1.23 (P = 0.032) and 35.9% vs. 19.4% (P = 0.04) respectively. Forty-three percent (31/72) of patients receiving vancomycin achieved clinical failure compared with 54.7% (29/53) of NVAMT patients (P = 0.197). Of the secondary outcomes analyzed, only readmission due to recurrence was significant between groups (vancomycin vs. NVAMT) – 13.8% vs. 30.2% (P = 0.026). In the univariate model only the choice of vancomycin met pre-defined criteria (P < 0.2) for inclusion in the multivariate model. In the multivariate analysis the choice of vancomycin was not found to be significant (0.71 (95% CI 0.33–1.52), P = 0.37).ConclusionVancomycin was not associated with an increased risk of clinical failure when compared with NVAMT in patients receiving OPAT.Disclosures All authors: No reported disclosures.

Upper Versus Lower Gastrointestinal Delivery for Transplantation of Fecal Microbiota in Recurrent or Refractory Clostridium difficile Infection: A Collaborative Analysis of Individual Patient Data From 14 Studies.

The aim of this study was to compare upper gastrointestinal (UGI) versus lower gastrointestinal (LGI) delivery routes of fecal microbiota transplantation (FMT) for refractory or recurrent/relapsing Clostridium difficile infection (CDI). FMT has been proven to be a safe and highly effective therapeutic option for CDI. Delivery, however, could be via the UGI or LGI routes, and it is unclear as to which route provides better clinical outcome. A systematic search for studies that reported the use of FMT for CDI treatment was conducted. Individual patient data that included demographic (age and sex) and clinical (route of FMT delivery, CDI outcome after FMT, and follow-up time) information were obtained. Kaplan-Meier cumulative hazard curves and Cox proportional hazard models were used to assess clinical failure after FMT by the route of delivery. Data from 305 patients treated with FMT (208 via LGI route and 97 via UGI route) for CDI were analyzed. At 30 and 90 days, the risk of clinical failure was 5.6% and 17.9% in the UGI group compared with 4.9% and 8.5% in the LGI delivery route group, respectively. A time-varying analysis suggested a 3-fold increase in hazard of clinical failure for UGI delivery (hazard ratio, 3.43; 95% confidence interval, 1.32-8.93) in the period after 30 days. FMT delivered via the LGI seems to be the most effective route for the prevention of recurrence/relapse of CDI. A randomized controlled trial is necessary to confirm whether FMT delivered via the LGI is indeed superior to that delivered via the UGI route.

Impact of fluconazole susceptibility on the outcome of patients with candidaemia: data from a population-based surveillance

ObjectivesThe clinical correlation of fluconazole antifungal susceptibility testing (AST) for Candida isolates and its integration with pharmacokinetics/pharmacodynamics (PK/PD) parameters is unclear. We analysed the impact of fluconazole minimum inhibitory concentration (MIC) values, 24-hour area under the concentration–time curve (AUC24) and AUC24/MIC ratio on the outcome of candidemic patients. MethodsWe included 257 episodes of candidaemia treated with fluconazole monotherapy for ≥72 hours from a population-based surveillance conducted in 29 hospitals (CANDIPOP Project). AST was centrally performed by European Committee on Antimicrobial Susceptibility Testing (EUCAST) and Clinical and Laboratory Standards Institute (CLSI) microdilution methods. Primary outcome was clinical failure (30-day mortality and/or persistent candidaemia for ≥72 hours from initiation of therapy). Secondary outcomes included early (3–7 days) and late (3–30 days) mortality. ResultsRates of clinical failure, early and late mortality among evaluable episodes were 32.3% (80/248), 3.1% (8/257) and 23.4% (59/248). There was no relationship between fluconazole MIC values or PK/PD parameters and clinical failure. Although MIC values ≥2 mg/L by EUCAST (positive predictive value 32.1%, negative predictive value 68.7%) and ≥0.5 mg/L by CLSI (positive predictive value 34.8%, negative predictive value 74.4%) appeared to be optimal for predicting clinical failure, no significant associations remained after multivariate adjustment (odds ratio 1.67; 95% confidence interval 0.48–5.79; p 0.423). Lack of association was consistent for alternative thresholds (including proposed clinical breakpoints). The only association found for secondary outcomes was between an AUC24/MIC ratio >400 h by CLSI and early mortality (odds ratio 0.18; 95% confidence interval 0.04–0.98; p 0.026). ConclusionsHigh fluconazole MIC values did not negatively impact outcome of patients with candidaemia treated with fluconazole. No effect of PK/PD targets on the risk of clinical failure was found.