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We studied 31 US healthcare facilities to characterize trends in mycobacterial testing. During 2009-2015, testing for acid-fast bacilli increased 3.2% annually, and prevalence of pathogenic nontuberculous mycobacteria increased 4.5% annually. These increases were highest for subpopulations at high risk of infection, including older women, Asians, and patients with concurrent conditions.

Background Ceftazidime-avibactam has in vitro activity against some carbapenem-resistant gram-negative infections (GNIs), and therefore may be a useful alternative to more toxic antibiotics such as colistin. Understanding ceftazidime-avibactam uptake and usage patterns would inform hospital formularies, stewardship, and antibiotic development. Methods A retrospective cohort study assessed inpatient encounters in the Vizient database. Ceftazidime-avibactam and colistin administrations were categorized into presumed empiric (3 consecutive days of therapy or less with qualifying exclusions) versus targeted therapy (≥4 consecutive days of therapy) for presumed carbapenem-resistant GNIs. Quarterly percentage change (QPC) using modified Poisson regression and relative change in frequency of targeted ceftazidime-avibactam to colistin encounters was calculated. Factors associated with preferentially receiving targeted ceftazidime-avibactam versus colistin were identified using generalized estimating equations. Results Between 2015 quarter (q) 1 and 2017q4, ceftazidime-avibactam was administered 21 215 times across 1901 encounters. Inpatient prescriptions for ceftazidime-avibactam increased from 0.44/10 000 hospitalizations in 2015q1 to 7.7/10 000 in 2017q4 (QPC, +11%; 95% CI, 10–13%; P < .01), while conversely colistin prescriptions decreased quarterly by 5% (95% CI, 4–6%; P < .01). Ceftazidime-avibactam therapy was categorized as empiric 25% of the time, targeted 65% of the time, and indeterminate 10% of the time. Patients with chronic kidney disease were twice as likely to receive targeted ceftazidime-avibactam versus colistin (RR, 2.02; 95% CI, 1.82–2.25), whereas those on dialysis were less likely to receive ceftazidime-avibactam than colistin (RR, 0.71; 95% CI, .61–.83). Conclusions Since approval in 2015, ceftazidime-avibactam use has grown for presumed carbapenem-resistant GNIs, while colistin has correspondingly declined. Renal function drove the choice between ceftazidime-avibactam and colistin as targeted therapy.

Background Invasive candidiasis (IC) is a growing concern among US healthcare facilities. A large-scale study evaluating incidence and trends of IC in the United States by species and body site is needed to understand the distribution of infection. Methods An electronic medical record database was used to calculate incidence and trends of IC in the United States by species and infection site from 2009 through 2017. Hospital incidence was calculated using total unique inpatient hospitalizations in hospitals reporting at least 1 Candida case as the denominator. IC incidence trends were assessed using generalized estimating equations with exchangeable correlation structure to fit Poisson regression models, controlling for changes in hospital characteristics and case mix over time. Results Candida albicans remains the leading cause of IC in the United States, followed by Candida glabrata. The overall incidence of IC was 90/100 000 patients, which did not change significantly over time. There were no changes in incidence among C. albicans, C. glabrata, C. parapsilosis, or C. tropicalis; the incidence of other Candida spp. as a whole increased 7.2% annually. While there was no change in candidemia 2009–2017, abdominal and nonabdominal sterile site IC increased significantly. Conclusions Nonbloodstream IC is increasing in the United States. Understanding the epidemiology of IC should facilitate improved management of infected patients.

Background: Delayed or in vitro inactive empiric antibiotic therapy may be detrimental to survival in patients with bloodstream infections (BSIs). Understanding the landscape of delayed or discordant empiric antibiotic therapy (DDEAT) across different patient, pathogen, and hospital types, as well as by their baseline resistance milieu, may enable providers, antimicrobial stewardship programs, and policy makers to optimize empiric prescribing. Methods: Inpatients with clinically suspected serious infection (based on sampling of blood cultures and receiving systemic antibiotic therapy on the same or next day) found to have BSI were identified in the Cerner Healthfacts EHR database. Patients were considered to have received DDEAT when, on culture sampling day, they received either no antibiotic(s) or none that displayed in vitro activity against the pathogenic bloodstream isolate. Antibiotic-resistant phenotypes were defined by in vitro resistance to taxon-specific prototype antibiotics (eg, methicillin/oxacillin resistance in S. aureus) and were used to estimate baseline resistance prevalence encountered by the hospital. The probability of DDEAT was examined by bacterial taxon, by time of BSI onset, and by presence versus absence of antibiotic-resistance phenotypes, sepsis or septic shock, hospital type, and baseline resistance. Results: Of 26,036 assessable patients with a BSI at 131 US hospitals between 2005 and 2014, 14,658 (56%) had sepsis, 3,623 (14%) had septic shock, 5,084 (20%) had antibiotic-resistant phenotypes, and 8,593 (33%) received DDEAT. Also, 4,428 (52%) recipients of DDEAT received no antibiotics on culture sampling day, whereas the remaining 4,165 (48%) received in vitro discordant therapy. DDEAT occurred most often in S. maltophilia (87%) and E. faecium (80%) BSIs; however, 75% of DDEAT cases and 76% of deaths among recipients of DDEAT collectively occurred among patients with S. aureus and Enterobacteriales BSIs. For every 8 bacteremic patients presenting with septic shock, 1 patient did not receive any antibiotics on culture day (Fig. 1A). Patients with BSIs of hospital (vs community) onset were twice as likely to receive no antibiotics on culture day, whereas those with bloodstream pathogens displaying antibiotic-resistant (vs susceptible) phenotypes were 3 times as likely to receive in vitro discordant therapy (Fig. 1B). The median proportion of DDEAT ranged between 25% (14, 37%) in eight Conclusions: Delayed or in vitro discordant empiric antibiotic therapy is common among patients with BSI in US hospitals regardless of hospital size, teaching status, or local resistance patterns. Prompt empiric antibiotic therapy in septic shock and hospital-onset BSI needs more support. Reliable detection of S. aureus and Enterobacteriales bloodstream pathogens and their resistance patterns earlier with rapid point-of-care diagnostics may mitigate the population-level impact of DDEAT in BSI.Funding: This study was funded in part by the National Institutes of Health Clinical Center, National Institutes of Allergy and Infectious Diseases, National Cancer Institute (NCI contract no. HHSN261200800001E) and the Agency for Healthcare Research and Quality.Disclosures: None

The prevalence and effects of inappropriate empirical antibiotic therapy for bloodstream infections are unclear. We aimed to establish the population-level burden, predictors, and mortality risk of in-vitro susceptibility-discordant empirical antibiotic therapy among patients with bloodstream infections.Our retrospective cohort analysis of electronic health record data from 131 hospitals in the USA included patients with suspected-and subsequently confirmed-bloodstream infections who were treated empirically with systemic antibiotics between Jan 1, 2005, and Dec 31, 2014. We included all patients with monomicrobial bacteraemia caused by common bloodstream pathogens who received at least one systemic antibiotic either on the day blood cultures were drawn or the day after, and for whom susceptibility data were available. We calculated the prevalence of discordant empirical antibiotic therapy-which was defined as receiving antibiotics on the day blood culture samples were drawn to which the cultured isolate was not susceptible in vitro-overall and by hospital type by using regression tree analysis. We used generalised estimating equations to identify predictors of receiving discordant empirical antibiotic therapy, and used logistic regression to calculate adjusted odds ratios for the relationship between in-hospital mortality and discordant empirical antibiotic therapy.21 608 patients with bloodstream infections received empirical antibiotic therapy on the day of first blood culture collection. Of these patients, 4165 (19%) received discordant empirical antibiotic therapy. Discordant empirical antibiotic therapy was independently associated with increased risk of mortality (adjusted odds ratio 1·46 [95% CI, 1·28-1·66]; p0·0001), a relationship that was unaffected by the presence or absence of resistance or sepsis or septic shock. Infection with antibiotic-resistant species strongly predicted receiving discordant empirical therapy (adjusted odds ratio 9·09 [95% CI 7·68-10·76]; p0·0001). Most incidences of discordant empirical antibiotic therapy and associated deaths occurred among patients with bloodstream infections caused by Staphylococcus aureus or Enterobacterales.Approximately one in five patients with bloodstream infections in US hospitals received discordant empirical antibiotic therapy, receipt of which was closely associated with infection with antibiotic-resistant pathogens. Receiving discordant empirical antibiotic therapy was associated with increased odds of mortality overall, even in patients without sepsis. Early identification of bloodstream pathogens and resistance will probably improve population-level outcomes.US National Institutes of Health, US Centers for Disease Control and Prevention, and US Agency for Healthcare Research and Quality.

Summary Background Clindamycin is strongly recommended as an adjunctive treatment to β-lactam antibiotics in patients with severe invasive group A β-haemolytic streptococcal (iGAS) infections. However, there is little evidence of a benefit in the use of clindamycin in humans, and its role, if any, in treating patients with invasive non-group A/B β-haemolytic streptococcal (iNABS) infections is unclear. Methods For this retrospective multicentre cohort study, we used a dataset from patients in the Cerner Health Facts database, which contains electronic health-based data from 233 US hospitals. We queried the Cerner Health Facts database for inpatients (no age restriction) admitted to hospital in 2000–15, with any clinical cultures positive for β-haemolytic streptococcal taxa of interest, and who had received β-lactam antibiotics within 3 days either side of culture sampling. This group of patients was then queried for those who had also received intravenous or oral clindamycin within 3 days either side of culture sampling. Patients were excluded if they had polymicrobial growth or clindamycin non-susceptible isolates, received linezolid, or had missing variable data needed for analysis. Patients were categorised by Lancefield group (iGAS or iNABS); β-lactam antibiotic-treated patients who had received clindamycin were propensity-matched (1:2) to those who did not receive clindamycin separately for iGAS and iNABS cohorts, and logistic regression was then used to account for residual confounding factors. The primary outcome was the adjusted odds ratio (aOR) of in-hospital mortality in propensity-matched patients treated with adjunctive clindamycin versus those not treated with clindamycin in the iGAS and iNABS infection cohorts. Findings We identified 1956 inpatients with invasive β-haemolytic streptococcal infection who had been treated with β-lactam antibiotics across 118 hospitals (1079 with iGAS infections and 877 with iNABS infections). 459 (23·4%) of these patients had received adjunctive clindamycin treatment (343 [31·7%] patients with iGAS infections and 116 [13·2%] patients with iNABS infections). The effect of adjunctive clindamycin therapy on in-hospital mortality differed significantly and showed the opposite trend in iGAS and iNABS infection cohorts (p=0·013 for an interaction). In the iGAS cohort, in-hospital mortality in propensity-matched patients who received adjunctive clindamycin (18 [6·5%] of 277 patients) was significantly lower than in those who did not (55 [11·0%] of 500 patients; aOR 0·44 [95% CI 0·23–0·81]). This survival benefit was maintained even in patients without shock or necrotising fasciitis (six [2·6%] of 239 patients treated with adjunctive clindamycin vs 27 [6·1%] of 422 patients not treated with adjunctive clindamycin; aOR 0·40 [0·15–0·91]). By contrast, in the iNABS infection cohort, in-hospital mortality in propensity-matched patients who received adjunctive clindamycin (ten [9·8%] of 102) was higher than in those who did not (nine [4·6%] of 193), but this difference was not significant (aOR 2·60 [0·94–7·52]). Several subset analyses found qualitatively similar results. Interpretation Real-world data suggest that increased use of adjunctive clindamycin for invasive iGAS infections, but not iNABS infections, could improve outcomes, even in patients without shock or necrotising fasciitis. Funding Intramural Research Program of the National Institutes of Health Clinical Center and the National Institute of Allergy and Infectious Disease.

Summary Background Evidence-based needs assessments for novel antibiotics against highly-resistant Gram-negative infections (GNIs) are scarce. We aimed to use real-world data from an electronic health record repository to identify treatment opportunities in US hospitals for GNIs resistant to all first-line drugs. Methods For this retrospective cohort study, population estimates with an unmet need for novel Gram-negative antibiotics were quantified using the Cerner Health Facts database (2009–15), aggregating episodes of infection in US hospitals with pathogens displaying difficult-to-treat resistance (DTR; resistance to carbapenems, other β-lactams, and fluoroquinolones) and episodes involving empirical coverage with reserve drugs (colistin or polymyxin B and aminoglycosides). Episodes displaying extended-spectrum cephalosporin resistance (ECR) were also estimated. Episodes were multiplied by site-specific and fixed 14-day treatment durations for conservative and liberal days-of-therapy (DOT) estimates and stratified by site and taxon. Hospital type-specific DOT rates were reliability adjusted to account for random variation; cluster analyses quantified contribution from outbreaks. Findings Across 2 996 271 inpatient encounters and 134 hospitals, there were 1352 DTR-GNI episodes, 1765 episodes involving empirical therapy with colistin or polymyxin B, and 16 632 episodes involving aminoglycosides. Collectively, these yielded 39·0 (conservative estimate) to 138·2 (liberal estimate) DOT per 10 000 encounters for a novel DTR-GNI-targeted drug, whereas greater treatment opportunities were identified for ECR (six times greater) and β-lactam susceptible GNIs (70 times greater). The most common DTR-GNI site and pathogen was lower respiratory (14·3 [43·3%] of 33 DOT per 10 000 encounters) and Pseudomonas aeruginosa (522 [38·1%] of 1371 episodes), whereas Enterobacteriaceae urinary-tract infections dominated the ECR or carbapenem-sparing niche (59·0% [5589 of 9535 episodes]) equating to 210·7 DOT per 10 000 encounters. DTR Stenotrophomonas maltophilia, Burkholderia spp, and Achromobacter spp represented less than 1 DOT per 10 000 encounters each. The estimated need for DTR-GNI-targeted antibiotics saw minor contributions by outbreaks and varied from 0·5 to 73·1 DOT per 10 000 encounters by hospital type. Interpretation Suspected or documented GNIs with no or suboptimal treatment options are relatively infrequent. Non-revenue-based strategies and innovative trial designs are probably essential to the development of antibiotics with improved effectiveness for these GNIs. Funding Center for Drug Evaluation and Research, US Food and Drug Administration; Intramural Research Program, National Institutes of Health Clinical Center and the National Institute of Allergy and Infectious Diseases and the National Cancer Institute.

At 128 US hospitals, from 2009–2014, a 17% decline occurred annually in central venous catheter tips sent for culture: a 6-fold decrease from blood culture sampling trends. The positive predictive value was low (23%). Tip culture use often does not conform to recommendations and offers limited independent treatment opportunities.

BACKGROUND: Resistance to all first-line antibiotics necessitates the use of less effective or more toxic “reserve” agents. Gram-negative bloodstream infections (GNBSIs) harboring such difficult-to-treat resistance (DTR) may have higher mortality than phenotypes that allow for ≥1 active first-line antibiotic. METHODS: The Premier Database was analyzed for inpatients with select GNBSIs. DTR was defined as intermediate/resistant in vitro to all ß-lactam categories, including carbapenems and fluoroquinolones. Prevalence and aminoglycoside resistance of DTR episodes were compared with carbapenem-resistant, extended-spectrum cephalosporin-resistant, and fluoroquinolone-resistant episodes using CDC definitions. Predictors of DTR were identified. The adjusted relative risk (aRR) of mortality was examined for DTR, CDC-defined phenotypes susceptible to ≥1 first-line agent, and graded loss of active categories. RESULTS: Between 2009–2013, 471 (1%) of 45011 GNBSI episodes at 92 (53.2%) of 173 hospitals exhibited DTR, ranging from 0.04% for Escherichia coli to 18.4% for Acinetobacter baumannii. Among patients with DTR, 79% received parenteral aminoglycosides, tigecycline, or colistin/polymyxin-B; resistance to all aminoglycosides occurred in 33%. Predictors of DTR included urban healthcare and higher baseline illness. Crude mortality for GNBSIs with DTR was 43%; aRR was higher for DTR than for carbapenem-resistant (1.2; 95% confidence interval, 1.0–1.4; P = .02), extended-spectrum cephalosporin-resistant (1.2; 1.1–1.4; P = .001), or fluoroquinolone-resistant (1.2; 1.0–1.4; P = .008) infections. The mortality aRR increased 20% per graded loss of active first-line categories, from 3–5 to 1–2 to 0. CONCLUSION: Nonsusceptibility to first-line antibiotics is associated with decreased survival in GNBSIs. DTR is a simple bedside prognostic measure of treatment-limiting coresistance.

Background Assessing the unmet need for novel antibiotics could inform appropriate utilization, enrollment in trials and ensure balance in aligning incentives and investments in therapeutic development. Methods The Cerner Healthfacts electronic health record repository was queried to identify inpatient treatment opportunities for Gram-negative active agents (GNAA) displaying either difficult-to-treat resistance (DTR; resistance to all β-lactams including carbapenems and fluoroquinolones) or extended-spectrum cephalosporin resistance (ECR). The former was quantified by aggregating episodes of confirmed DTR infection (i.e., DTR strain isolated and concomitant antibiotic(s) received) or suspected (i.e., 1–2 days of empiric colistin/polymyxin-B or aminoglycosides and no DTR pathogen isolated). Aggregate days of therapy (DOT) were reported as a range, multiplying episodes by site-specific or uniform 14-day treatment durations, respectively. Recursive partition and cluster analyses were performed for hospital characteristics and contributions of outbreaks to DTR treatment opportunities, respectively. Results Between 2009 and 2015, across 2,996,271 encounters, 1,352 episodes of potential targeted treatment were identified, which combined with empiric treatment episodes, represent 39–138 DOT/10,000 encounters for a DTR-GNAA. Similarly, 9,535 episodes of potential targeted therapy for an ECR-GNAA were identified (representing 211-466 DOT/10,000 encounters). The most common candidate site and pathogens for DTR-GNAA were lower respiratory and A. baumannii and P. aeruginosa respectively; DTR bloodstream infections displayed the highest crude mortality at 45%. Enterobacteriaceae urinary infections dominated the ECR group. Teaching hospitals with ≥100 beds were the most likely to encounter a DTR infection; potential outbreaks contributed to 10.6% of DTR treatment opportunities. Conclusion The candidate population for new antibacterials directed against highly resistant GN infections with limited treatment options is small but critical, indicating a role for non-revenue-based strategies to develop more effective antibiotics, as well as mechanisms to support trials that address real-world unmet needs. Disclosures All authors: No reported disclosures.

Background Difficult-to-treat resistance (DTR) is a metric for clinically relevant “pan-resistance” to available high-efficacy, low-toxicity antibiotic treatment options at any given time. Previous DTR prevalence estimates in Gram-negative (GN) bloodstream isolates from 2009 to 2014 have ranged between 1 and 1.5%. We sought to estimate the national burden of DTR GN isolates and more recent trends by region, site, and species. Methods Clinical cultures with GN isolates were identified from inpatient encounters in hospitals reporting at least one culture with susceptibility testing for a given month to Premier Healthcare Database or Cerner Health Facts Database from 2012 to 2017. DTR was defined as intermediate susceptibility or resistance to all tested carbapenems, other β-lactams, and fluoroquinolones, but not including agents introduced 2014 onwards. For each year, a raking procedure generated weights to extrapolate the sample estimate to match American Hospital Association distributions based on US census division, hospital bed capacity, teaching status, and urban designation. A weighted means survey procedure was used to extrapolate the sample estimate to obtain national DTR burden. Trends in DTR incidence were examined by using weighted multivariable logistic regression. Results Extrapolating from a 373-hospital sample, the estimated 2017 US inpatient burden of DTR isolates was 3,315 (1.3%) among sterile-site and 31,509 (1.7%) among all cultures, ranging from 0.5% to 3.3% in Mountain and New England regions respectively. P. aeruginosa was the most common species overall (37%), while A. baumannii was most common among sterile sites (31%). Between 2012 and 2017, there was no annual percent change in DTR incidence for sterile sites [OR 0.99 (0.93, 1.06)] but for all cultures it decreased 4.1% annually [OR 0.95 (0.91, 0.99)], including 9% annually for A. baumannii [OR 0.905 (0.860, 0.953)] and K. pneumonia [OR 0.903 (0.824, 0.991)], respectively. Conclusion The US inpatient burden of GN isolates displaying DTR is relatively low, varies by region, and has remained stable or declined slightly in recent years. Periodic inclusion of emerging antibiotics in the DTR classification will allow for a dynamic index between resistance and available agents. Disclosures All Authors: No reported Disclosures.

Background Clindamycin suppresses invasive β-hemolytic streptococcal (iBHS) toxin production and its cidality, unlike β-lactams, is independent of bacterial inoculum. Evidence favoring the use of adjunctive clindamycin in iBHS is predominantly from in vitro and animal studies. Clinical studies, limited to single-center series or active surveillance, have yielded mixed results. Furthermore, its role in infections caused by non–group A or B β-hemolytic streptococci (NABS) remains poorly defined. Previously we were unable to demonstrate a clindamycin survival benefit in patients with group A streptococci (GAS) bacteremia. Here we examined the impact of adjunctive clindamycin on survival among patients with either invasive GAS or NABS infections from all sites. Methods Clinical characteristics, in vitro susceptibility and antibiotic therapy were examined for unique inpatient encounters with iBHS (GAS + NABS) infections in the Cerner HealthfactsTM Database. β-Lactam treated cases receiving clindamycin were matched 1:1 to non-clindamycin cases by propensity of receiving clindamycin using nearest neighbor propensity score matching with downstream adjustment using logistic regression. In-hospital mortality, length of stay (LOS) and Sequential Organ Failure (SOFA) score trajectory was compared based on the matched sample. Results Of 1,956 inpatients with iBHS infection treated with β-lactams at 118 hospitals between 2000 and 2015, 459 (23.5%) received adjunctive clindamycin. Propensity score matching generated 389 case-pairs with good covariate balance (Table 1, Figure 1). In-hospital mortality did not differ between matched clindamycin and non-clindamycin cases (7.2% vs. 8.0%, P = 0.66, aOR 0.88, [95% CI .49–1.57]) (Figure 2). Receipt of clindamycin early (within 24h vs. no clindamycin) also did not display a survival advantage (aOR 1.04 [0.51–2.14]). On day 4 of therapy Median SOFA score (P = 0.586) and SOFA delta (day 0–day 4) were similar between the two groups (P = 0.13; Figure 3). Amongst survivors, median [IQR] LOS was greater in the clindamycin group (8[5,12] vs. 6[4,9]; P = 0.001) Conclusion Adjunctive clindamycin was not associated with decreased mortality or degree of organ dysfunction among patients with iBHS infection already treated with β-lactams. Figure 2: Odds Ratio of In-Hospital Mortality Abbreviations: GAS: Group A Streptococcus , ICU: intensive care unit, iβHS: invasive β-Hemolytic streptococcus, NABS: Non group A β-Hemolytic streptococci , OR: odds ratio Figure 2 Legend: The figure reports the odds ratios (ORs) of in-hospital mortality and 95% confidence intervals in the unmatched and unadjusted analysis, matched and unadjusted analysis, and primary analysis of all propensity-matched pairs with downstream adjustment with logistic regression for proven ißHS, vasopressor use and ICU (within 24h of culture sampling), as well as sensitivity analyses on propensity matched pairs of 2:1 match and subgroup analysis on propensity matched pairs of (1) proven ißHS alone (2) probable ißHS alone (3) ICU admission (within 24h of culture sampling) (4) patients receiving vasopressor therapy (within 24h of culture sampling) (5) Group A ißHS alone (6) Non Group A ißHS alone. There was no statistically significant difference in the ORs for in-hospital mortality between clindamycin and propensity-matched non-clindamycin cases in the primary analysis (*) as well as all sensitivity and subgroup (†) analyses. Figure 3: SOFA Score Trajectory by Survival Status Abbreviations: B: Non-Clindamycin cases, BC: Clindamycin Cases Figure 3 Legend: SOFA score by day of therapy of clindamycin and non-clindamycin matched cases based on survival status from day zero (day prior to antibiotic therapy) to day four of therapy. The linear mixed models were used to assess the time trends and the clindamycin effect on the longitudinal SOFA scores. SOFA trajectory was examined for the post matching sample. Square root transformation was applied to the SOFA score to meet the normality assumption Mean Baseline SOFA scores prior to therapy were similar amongst clindamycin and non-clindamycin subjects (mean [standard deviation(SD)] SOFA score: 1.88[2.48] vs. 1.96[2.60]; p= 0.634). On day 4 of therapy SOFA scores were similar between remaining 310 clindamycin and 286 non-clindamycin hospitalized patients (mean[SD] SOFA score: 1.79[2.88] vs. 1.67 [2.49]; p=0.586). The SOFA delta (day 0 SOFA score - day 4 SOFA score) was similar between the two groups (p=0.1331). When examined amongst survivors only, SOFA scores on day 4 of therapy were similar between and 272 non-clindamycin and 310 clindamycin hospitalized patients (mean[SD] SOFA score: 1.45 [2.20] vs. 1.52 [2.44]) This work was funded in part by the Intramural Research Program of the National Institutes of Health Clinical Center and the National Institute of Allergy and Infectious Diseases. The opinions expressed in this abstract are those of the authors and do not represent any position or policy of the National Institutes of Health, the United States Department of Health and Human Services, or the United States government. Disclosures All authors: No reported disclosures.

Background Serum procalcitonin (PCT) may aid in early detection and treatment of bacterial bloodstream infections (BSI), yet evidence for this indication is inconclusive. We leveraged real-world data to examine biological variability in PCT across host and pathogen factors and its utility for ruling out BSI on admission. Methods PCT measurements within 24 hours of admission were examined in patients presenting with monomicrobial BSI to 250 hospitals in the Cerner Healthfacts Database. The reliability of admission PCT for ruling out BSI at hospital presentation was assessed using two different thresholds ( Results Between 2007 and 2017, PCT was measured on admission in 4,358/42,465 (10.3%) adults with BSI present on admission at 60 hospitals. Of these, 870 (20%) met CDC surveillance criteria for sepsis. The median admission PCT was 4.89 [0.93, 23.98] and varied by taxon, BSI source, patient temperature, and the presence and severity of sepsis; acute illness severity was the greatest driver of high PCT levels (Fig 1). Using a threshold of ≥ 0.50 ng/mL, the sensitivity of PCT for detection of BSI was 84% for all patients. Notably, BSI without sepsis was 4-fold more likely to yield a false negative PCT ( Conclusion PCT levels and the reliability of this test for ruling out bacteremia at hospital presentation varies by pathogen, presenting signs, and presence vs. absence of sepsis. Disclosures All authors: No reported disclosures.

Background Ceftazidime–avibactam (CAV) was US FDA-approved for complicated intra-abdominal/urinary tract infections in 2015, and for hospital-acquired/ventilator-associated pneumonia in 2018. However, little is known about its real-world use. Methods Encounters of inpatients receiving CAV at academic hospitals in the VizientTM Clinical Resource Manager were identified (CAV encounters). CAV administered for ≤2 consecutive days during an encounter or any duration of CAV within 2 days of admission (excluding acute care hospital transfers) was considered empiric therapy. Targeted therapy was defined as ≥4 consecutive days or death within 2 days of therapy; empiric and targeted therapy cohorts were mutually inclusive. CAV-encounter characteristics, use patterns and Infectious Disease (ID) consultation were examined. Quarterly hospital uptake of CAV and % change in CAV encounter prevalence (using Poisson regression) were calculated. Results From January 2015 to December 2017, 20,590 CAV doses occurred in 2,128 encounters among 1,652 patients. Mean duration of therapy was 8 ± 7.9 days (range 1–86); overall mortality was 24%. The number of hospitals prescribing CAV increased from 5 to 92/168 and quarterly prevalence of CAV encounters increased from 5/10,000 hospitalizations in 2015q1 to 9.8 in 2017q4 (% change=2.1[0.7–3.6] %/quarter; (P = 0.004). Therapy was empiric in 904 (42%) encounters and targeted in 1,472 (69%); 63% of empiric CAV was initiated within 2 days of admission. CAV was initiated in the ICU in 862 (40.5%) encounters. Infection site was coded as respiratory in 34%, urinary in 26% and abdominal in 16% of encounters. Within 31 hospitals reporting consultant specialty, 29% of targeted therapy occurred without ID consultation. For targeted therapy encounters, CAV monotherapy occurred in 841 (57%) and combination therapy in 631 (43%) encounters, which most often included aminoglycosides, colistin or tigecycline. Mortality was 22% in the monotherapy and 25% in the combination therapy group (P = 0.08). Conclusion CAV use across US academic medical centers has increased modestly over 3 years. More than 40% of CAV prescriptions appear to be empiric and targeted therapy often occurs without ID consultation at academic centers. Disclosures All authors: No reported disclosures.

Background Tick-borne diseases are increasing in incidence in the United States; however, limited data exist on regional trends of associated hospitalizations. Using a nationally distributed dataset of US hospital-based medical records, we aimed to assess trends in incidence of hospitalizations from tick-borne disease by geographic region. Methods Data were examined from 156 US hospitals from 2009 to 2014 to identify hospitalizations with tick-borne disease. Cases were described and Poisson regression used to estimate the annual percent change (APC) and associated 95% confidence intervals (CI) in incidence by region over time. Results Overall, 2,543 hospitalized patients with tick-borne disease were identified (average annual incidence = 28.4 cases/100,000 hospitalized persons), including 1,613 (63%) with Lyme disease, 379 (15%) tick-borne fever, 293 (12%) ehrlichiosis, 93 (4%) babesiosis, 43 (2%) rickettsiosis, and 122 (4%) multiple tick-related diagnoses. Tick-borne diseases varied significantly by region, with Lyme disease more frequent in those residing in the Northeast (68%) than the South (57%) or West (42%) and tick-borne fever more common in the West (28%) vs. the South (18%), Midwest (14%), and Northeast (13%) (P < 0.0001). Significant increases in tick-borne disease hospitalizations were identified across nearly all US regions, ranging from 15% per year in the South (95% CI=8–24%) to 45% per year in the West (34–58%), with the exception of the Northeast, where incidence declined by 6% per year (0.04–11%). Lyme disease hospitalizations showed similar trends, with the greatest increase in the South (APC = 53%, 95% CI = 33–76%) and a decrease in the Northeast (APC = 13%; 3%–23%). Hospitalizations with tick-borne fever increased in the Midwest (APC = 49%; 8–206%) and Northeast (APC = 18%; 4–34%); with ehrlichiosisincreased in the West (APC = 231%; 75–306%); and with babesiosis increased in the South (APC = 50%; 12–201%) and the Midwest (APC = 21%; 5–39%). Conclusion Incidence of hospitalizations from tick-borne disease is increasing throughout much of the nation, except in the Northeast where decreases in Lyme disease were observed. While hospitalizations with tick-borne diseases remain rare, the increases noted are substantial and may reflect rising incidence of these diseases within the represented states. Disclosures All authors: No reported disclosures.

Background The prevalence of nontuberculous mycobacterial pulmonary disease (NTM PD) is increasing in the United States and globally. The reasons for this increase are not clear but could be related to both gained awareness leading to increased mycobacterial testing, or to a true NTM PD increase. To further examine the role of testing rates in the observed increase, we studied trends in Acid-Fast Bacteria (AFB) testing and NTM isolation positivity using a large Electronic Health Record (EHR) dataset in the United States. Methods Using the Cerner Health Facts EHR dataset, we extracted microbiologic, demographic, and clinical data for patient encounters (inpatient or outpatient), with ≥1 orders for AFB respiratory cultures. The analysis was limited to the 43 facilities reporting continuously for the period 2009–2015. A patient with at least one AFB test was considered tested (AFB) and a patient with at least one pathogenic NTM respiratory isolate was considered positive. Trends in AFB testing and NTM positivity were estimated using log-linked Poisson regression (P < 0.05). Results From 2009 through 2015, of 14.8 million patients, 65,010 had 142,315 AFB tests, averaging 2.2 AFB tests/patient, for an overall testing prevalence of 0.43%; the annual testing prevalence remained unchanged during the study period (P = 0.44) (Figure 1). Of the 65,010 patients with AFB tests, 3,942 (6.1%) had ≥1 pathogenic NTM species, for an overall pulmonary NTM isolation prevalence of 2.7/10,000 patients represented in Cerner Health Facts dataset. Of the patients that had at least one pathogenic NTM, 3,094 (78%) had M. avium complex, and 265 (7%) had M. abscessus/chelonae, (Figure 2). Among patients with at least 1 NTM-positive culture, 138 patients had concomitant growth of M. tuberculosis. Conclusion Increases in NTM PD are not explained by increases in AFB testing, which remained constant in the population represented here. This study was funded in part by the Division of Intramural Research, NIAID, NIH. Disclosures All authors: No reported disclosures.

The in vitro effects of abscisic acid (ABA) and nitric oxide (NO) on the nematode-trapping fungus Drechslerella stenobrocha AS6.1 were examined. The average number of traps (constricting rings) per colony and the percentage of nematodes (Caenorhabditis elegans) trapped were greatly increased by addition of ABA but greatly suppressed by addition of sodium nitroprusside (SNP, an NO donor) to corn meal agar. The suppressive effect of SNP was not negated by addition of an NO synthase competitive inhibitor (l-naphthylacetic acid, L-NNA) or an NO-specific scavenger [2-(4-carboxyphenyl)-4,4, 5,5-tetramethylimidazoline-1-oxyl-3-oxide, cPTIO]. When added without SNP, however, L-NNA and cPTIO caused moderate increases in trap number and trapping. The results indicate that the trap formation and nematode-trapping ability of D. stenobrocha were enhanced by ABA but decreased by exogenous NO.

Background While 50% of invasive candidiasis (IC) has historically been caused by C. albicans, the changing epidemiology and rise in drug-resistant Candida necessitates understanding the contribution of specific Candida species to IC. To date, species and site-specific trends in IC have not been reported on a large scale using US clinical data. Methods Using the Cerner Health Facts electronic health record (EHR) dataset, inpatient hospitalizations with any Candida spp. isolated from blood or a sterile site (SS) (abdominal or other) were identified from 2009 to 2015. Patient characteristics were described by species. Significant relationships (P ≤ 0.05) were assessed using chi-squared or exact binomial tests. Annual percent change in IC incidence by site and species were assessed via Poisson regression. Results Overall, 19,310 Candida isolates from 10,313 patients were identified. Of these, 46% of isolates were C. albicans, 22% C. glabrata, 14% C. parapsilosis, 7% C. tropicalis, and 11% other/unspeciated; no C. auris infections were identified. The overall incidence of IC was 99 cases/100,000 patients. Compared with C. albicans, isolation of other species was 35% more frequent from blood, and 43% and 30% less frequent from non-blood abdominal and non-abdominal SSs, respectively (Table 1). Total IC increased by 1% (95% CI = 0.2–2%) annually; while abdominal and SS IC significantly increased by 6% (4–8%) and 11% (9–13%) per year, respectively, candidemia decreased significantly by 4.5% (3–6%) annually. Among C. albicansinfections candidemia decreased by 6.5% (5–8%) annually, while abdominal (5%, 3–8%) and other SS infections (10%, 7–13%) increased (Figure 1). Candidemia incidence remained unchanged for the other species. SS infections increased for every species, and abdominal infections increased for all but C. parapsilosis (Figure 2). Conclusion In this first large-scale study on trends in IC using US hospital EHR data, the species distribution of IC isolates varied between blood and non-blood SSs. The incidence of candidemia is decreasing, but not for potentially drug-resistant species such as C. glabrata, which continue to pose treatment challenges. This work was supported in part by the Division of Intramural Research, NIAID, NIH Disclosures All authors: No reported disclosures.

Background In Gram-negative bacteremia (GNB), administrative data suggest that “difficult-to-treat resistance” (DTR; i.e., co-resistance to all first-line antibiotics) increases mortality. However, adequate risk-adjustment for severity of illness (SOI) may require granular laboratory and physiologic data. Methods Adult inpatients with GNB were identified from electronic health records (EHRs) of 140 hospitals in the Cerner Healthfacts database between 2009 and 2015. Mortality from DTR (intermediate/resistant in vitro to β-lactams including carbapenems and fluoroquinolones) was compared with GNB phenotypes susceptible to at least one first-line agent, but otherwise resistant to carbapenems (CR), extended-spectrum cephalosporins (ECR), or fluoroquinolones (FQR) per US Centers for Disease Control and Prevention surveillance definitions. Relative risk of mortality was adjusted (aRR) for age, sex, baseline Sequential Organ Failure Assessment (SOFA) score, Elixhauser comorbidity index, GNB source, taxon, hospital vs. community onset, year, and hospital region, bed capacity, and urban and teaching status using Poisson regression. Results Of 25,448 unique GNB encounters, 207 (1%) met DTR criteria. DTR patients were 2-fold more likely to receive intravenous colistin and 5-fold more likely to receive tigecycline compared with CR cases susceptible to ≥1 first-line agent. Crude mortality varied considerably by taxon and resistance phenotype, but resistance per se was associated with only a minority of overall deaths (DTR = 3% of deaths; any of the four resistance phenotypes = 28% of deaths; Figure 1). Inclusion of EHR-derived, baseline SOFA scores in SOI adjustments decreased aRR effect estimates; nonetheless, all resistance phenotypes still significantly increased mortality (Figure 2A). Among resistance phenotypes, aRR of mortality was similar for DTR vs. CR (aRR = 1.18; 95% CI, 0.91–1.54; P = 0.2), but higher for DTR vs. ECR (aRR = 1.26 [1.01–1.58]; P = 0.04), and DTR vs. FQR (aRR = 1.36 [1.08–1.70]; P = 0.008), respectively (Figure 2B). Conclusion DTR is associated with nonsurvival and greater use of reserve antibiotics in GNB, but adds little to the risk of death associated with CR. The impact of resistance on survival is attenuated but still present even after risk adjustment using granular clinical data. Disclosures All authors: No reported disclosures.

Background Discordance between in vitro susceptibility and empiric antibiotic therapy is inextricably linked to antibiotic resistance and decreased survival in bloodstream infections (BSI). However, its prevalence, patient- and hospital-level risk factors, and impact on outcome in a large cohort and across different pathogens remain unclear. Methods We examined in vitro susceptibility interpretations for bacterial BSI and corresponding antibiotic therapy among inpatient encounters across 156 hospitals from 2000 to 2014 in the Cerner Healthfacts database. Discordance was defined as nonsusceptibility to initial therapy administered from 2 days before pathogen isolation to 1 day before final susceptibility reporting. Discordance prevalence was compared across taxa; risk factors and its association with in-hospital mortality were evaluated by logistic regression. Adjusted odds ratios (aOR) were estimated for pathogen-, patient- and facility-level factors. Results Of 33,161 unique encounters with BSIs, 4,219 (13%) at 123 hospitals met criteria for discordant antibiotic therapy, ranging from 3% for pneumococci to 55% for E. faecium. Discordance was higher in recent years (2010–2014 vs. 2005–2009) and was associated with older age, lower baseline SOFA score, urinary (vs. abdominal) source and hospital-onset BSI, as well as ≥500-bed, Midwestern, non-teaching, and rural hospitals. Discordant antibiotic therapy increased the risk of death [aOR = 1.3 [95% CI 1.1–1.4]). Among Gram-negative taxa, discordant therapy increased risk of mortality associated with Enterobacteriaceae (aOR = 1.3 [1.0–1.6]) and non-fermenters (aOR = 1.7 [1.1–2.5]). Among Gram-positive taxa, risk of mortality from discordant therapy was significantly higher for S. aureus (aOR = 1.3 [1.1–1.6]) but unchanged for streptococcal or enterococcal BSIs. Conclusion The prevalence of discordant antibiotic therapy displayed extensive taxon-level variability and was associated with patient and institutional factors. Discordance detrimentally impacted survival in Gram-negative and S. aureus BSIs. Understanding reasons behind observed differences in discordance risk and their impact on outcomes could inform stewardship efforts and guidelines for empiric therapy in sepsis. Disclosures All authors: No reported disclosures.

Anthrax lethal toxin (LT) is a major virulence factor of Bacillus anthracis. LT challenge suppresses platelet counts and platelet function in mice, however, the mechanism responsible for thrombocytopenia remains unclear. LT inhibits cellular mitogen-activated protein kinases (MAPKs), which are vital pathways responsible for cell survival, differentiation, and maturation. One of the MAPKs, the MEK1/2-extracellular signal-regulated kinase pathway, is particularly important in megakaryopoiesis. This study evaluates the hypothesis that LT may suppress the progenitor cells of platelets, thereby inducing thrombocytopenic responses. Using cord blood-derived CD34(+) cells and mouse bone marrow mononuclear cells to perform in vitro differentiation, this work shows that LT suppresses megakaryopoiesis by reducing the survival of megakaryocytes. Thrombopoietin treatments can reduce thrombocytopenia, megakaryocytic suppression, and the quick onset of lethality in LT-challenged mice. These results suggest that megakaryocytic suppression is one of the mechanisms by which LT induces thrombocytopenia. These findings may provide new insights for developing feasible approaches against anthrax.