bluuebunny/crossref_metadata_2025 huggingface dataset:
1507. Pharmacodynamic Target Attainment of Daptomycin Against Staphylococcus aureus for Treatment of Pediatric Osteomyelitis
Authors: Stimes Grant , Girotto Jennifer E , Courter Joshua D
Published: October 2019

Background

Daptomycin (DAP) is lipopeptide that frequently is used to treat infections caused by Staphylococcus aureus in adult patients. There are limited data using daptomycin in pediatric patients for the treatment of osteomyelitis caused by S. aureus. This study’s objective is to describe pharmacodynamic (PD) target attainment of daptomycin in pediatric patients with osteomyelitis.

Methods

Medline was queried to obtain PD targets, pediatric pharmacokinetic models, and bone penetration information to build a model for DAP. A 10,000 subject Monte Carlo simulation was performed to estimate steady-state concentrations in the bone. Simulations modeled 30-minute infusions with using 12 mg/kg/dose IV q24h for patients less than 7 years and 10 mg/kg/dose IV q24h for patients 7 years and older. Goal PD targets were: AUC24: MIC of 666 μg hours/mL for log1 killing and AUC24: MIC of 1,061 for log2 killing. The CLSI breakpoint of 1 mg/L was used as a starting point and MIC’s were analyzed below that level.

Results

PD target attainment in percentages is listed for DAP below in Tables 1 and 2 and are separated by age groups of patients.

Conclusion

The studied DAP doses did not reach any PD target attainment at the CLSI breakpoint of 1 mg/L. Based on these data, DAP should not be empirically used to treat SA osteomyelitis unless the exact MIC is known. Furthermore, modern pediatric pharmacokinetic studies of DAP for pediatric osteomyelitis are warranted.

Disclosures

All authors: No reported disclosures.
1512. Treatment of Staphylococcus aureus Bacteremia in a Pediatric Population: A Retrospective Cohort Analysis
Authors: Gunter Sarah G , Stover Kayla R , Barber Katie , Wagner Jamie , Joyce Wingler Mary , Cretella David A
Published: October 2019

Background

Staphylococcus aureus bacteremia (SAB) is a well-known cause of morbidity in pediatric patients; however, limited data are available regarding optimal antimicrobial therapy. The purpose of this study was to assess treatment outcomes associated with intravenous (IV) vs. oral (PO) stepdown treatment of SAB in a pediatric population.

Methods

This study evaluated patients who were admitted between July 2012 and August 2018, between the ages of 3 months and 18 years, had a blood culture positive for S. aureus, and received at least 72 hours of inpatient treatment. Exclusion criteria were as follows: pregnancy, death within 72 hours of initial culture, hospice/palliative care, polymicrobial bacteremia, and previous SAB within the study period. The primary endpoint was 30-day readmission rates. Secondary endpoints included hospital length of stay and all-cause inpatient mortality.

Results

In total, 101 patients were included (43 IV therapy alone; 58 PO stepdown). The median age was 7.9 years (IQR, 3.0, 12.2; range 4 months to 16.7 years), and 52.5% were male. The most common primary foci of infection were osteomyelitis (n = 32), device-associated infections (n = 23), and skin/soft-tissue infections (n = 8). Most patients (56.4%) had no comorbidities. There were no significant differences in comorbidities between groups except the IV group had significantly more immunosuppressed patients (30.2% vs. 1.7%; P < 0.001). Methicillin resistance was noted in 56.4% of patients (62.8% IV group vs. 51.7% PO stepdown; P = 0.313). The most common IV agents were vancomycin (n = 51) and anti-Staphylococcal penicillins (n = 21), while the most common PO agents were clindamycin (n = 29) and cephalexin (n = 20). Thirty-day readmission occurred in 25.6% (n = 10) of patients receiving full-course IV therapy and 5.3% (n = 3) in the PO stepdown group among survivors (P = 0.006; n = 96). Median length of stay was 11.0 days (IQR, 8.0, 21.0) in the IV group and 7.0 days (IQR, 5.0, 11.0) in the PO stepdown group (P = 0.001). All-cause inpatient mortality occurred in four patients (9.3%) in the IV group compared with one (1.7%) in the PO stepdown group (P = 0.160).

Conclusion

Patients in the PO stepdown group had a low rate of 30-day readmissions and had a significantly shorter hospital length of stay than patients who received a full IV course.

Disclosures

All authors: No reported disclosures.
1513. Management of Children with Blood Cultures (BC) Positive for Nonpathogenic Organisms After the Introduction of Polymerase Chain Reaction (PCR) Technology
Authors: Hughes Julianne , Barone Stephen
Published: October 2019

Background

Traditionally, clinicians would wait for the absence of growth in BC for 48 hours to consider a BC negative. A BC with a positive gram stain necessitated a repeat BC and antibiotics prior to final identification. Blood culture identification (BCID) PCR has the potential to shorten this time course, particularly with pathogens that are considered “contaminants.” There is no published data which addresses the clinical significance of more rapidly identifying contaminants.

Methods

This is a retrospective chart review of data collected from children (ages 2 months- 18 years) treated at Cohen Children’s Medical Center, who had a positive BC deemed a contaminant. A 2.5-year period prior to and after implementation of PCR technology was observed (September 2015–November 2018). A contaminant was defined as bacteria that is not considered virulent in an immunocompetent patient. Patients with indwelling catheters, those who have undergone corrective cardiac surgery or are immunocompromised were excluded from analysis. Data collected included length of stay, antibiotic duration and whether a patient received a repeat BC.

Results

136 patients during this time (49% (n = 67) pre-PCR and 51% (n = 69) post-PCR) had positive BC for nonvirulent bacteria. Patients in the pre-PCR period received BC only, while those in the post-PCR period received both BC and PCR, with all BC and PCR results being concordant. The proportion of patients who did not receive antibiotics was greater in the post-PCR group (70%, 48 of 69) compared with the pre-PCR group (45%, 30 of 67), P < 0.01. Of those who received antibiotics, the proportion of patients who received more than 1 dose was significantly lower in the post-PCR group (43%, 9 of 21) compared with the pre-PCR group (73%, 27 of 37), P < 0.025. The proportion of patients who had a repeat BC was significantly lower in the post-PCR group (58%, 40 of 69), compared with the pre-PCR group (82%, 55 of 67), P = 0.0022. The proportion of patients who were asked to return to the emergency department was significantly lower in the post-PCR group (59%, 16 of 27), compared with the pre-PCR group (88%, 23 of 26), P = 0.016.

Conclusion

With the addition of PCR technology, patients with BC positive for nonpathogenic bacteria have received less antibiotics, less repeat BCs and were less frequently asked to return for evaluation.#8232;

Disclosures

All authors: No reported disclosures.
1518. The Microbiology of Osteoarticular Infections in Patients with Sickle Hemoglobinopathies at Texas Children’s Hospital, 2011–2018
Authors: Ikeda Saki , Kaplan Julika , McNeil Jonathon C , Kaplan Sheldon L , Vallejo Jesus G
Published: October 2019

Background

Osteoarticular infections (OAI) are common in patients with major sickle hemoglobinopathies (Hemoglobin [Hgb] SS, Hgb SC, and Hgb Sβ thalassemia). Although Salmonella spp. cause a substantial number of OAIs in these patients, contemporary data regarding the most common etiology in the era of community-acquired methicillin-resistant Staphylococcus aureus (MRSA) are lacking. This introduces challenges for selecting empiric antimicrobial therapy. We evaluated the microbiology and management of OAI in children with sickle hemoglobinopathies.

Methods

Children with sickle hemoglobinopathies admitted to Texas Children’s Hospital with acute hematogenous OAI from 2011 to 2018 were identified based on ICD10 codes and the consult database of the pediatric infectious diseases service. Culture-negative cases were included if treated for OAI. Medical records were reviewed. Statistical analyses were conducted with STATA ver. 13.

Results

36 patients met inclusion criteria; 53% were diagnosed with isolated osteomyelitis and 47% with osteomyelitis and septic arthritis. In 42% a microbial etiology was identified (Figure 1) with Salmonella spp. being the most common (n = 7, 47%) followed by S. aureus (n = 5, 33%).11 (31%) patients had subperiosteal or intraosseous abscesses and 26 (72%) underwent diagnostic and/or therapeutic surgical procedures; 36% had positive blood cultures. Children with Salmonella spp. infections had a longer duration of fever (median-5, range: 4–9 days) compared with those caused by other pathogens (median-2, range: 0–6 days; P = 0.04). The median duration of IV therapy was longer in culture-positive than culture-negative cases (30 vs.10 days, P = 0.009); the total duration of therapy was similar for all cases (32 days, IQR: 28–42). No patients were readmitted due to OAI.

Conclusion

At our institution, Salmonella spp. were the most common cause of OAI among children with sickle hemoglobinopathies. Subperiosteal/intraosseous abscess formation and the need for surgical procedures were common. The role of oral antibiotics for the treatment of Salmonella OAI in patients with sickle hemoglobinopathies warrants further study.

Disclosures

All authors: No reported disclosures.
1526. Epidemiology of and Risk Factors for Nontyphoidal Salmonella Bacteremia in Children: A 20-Year Retrospective Cohort
Authors: Greenhow Tara L
Published: October 2019

Background

Nontyphoidal Salmonella (NTS) infections are the most common culture-confirmed foodborne illness in the United States. One to five percent of enteric infections due to NTS result in bloodstream infection (BSI). Host risk factors for NTS BSI include extremes of age and chronic or immunosuppressing conditions.

Methods

This was a retrospective review of the electronic health records (EHRs) of all blood cultures collected from January 1, 1999 to December 31, 2018 at Kaiser Permanente Northern California (KPNC) positive for Salmonella spp. The speciation and group of all Salmonella spp. were extracted from the microbiology records. Using KPNC population data, the incidence rate of NTS BSI by age and year of infection was calculated. Using a test for trend, the trend in rates of NTS BSI was determined. Risk factors for complicated NTS BSI using clinical and laboratory data were calculated.

Results

From 1999 to 2018, there were 212 cases of NTS BSI and 104 cases of Salmonella typhi and paratyphi BSI. The average number of cases per year was 10.6 (range 3–25). There were 14,952,802 evaluable children over the 20 years, with an average of 747,640 per year. The incident rate of NTS bacteremia was 1.4 per 100,000 children per year. The trend to increasing cases was not statistically significant (Figure 1). The distribution of NTS BSI cases were 114 (54%) Group B, 33 (15.5%) Group C, 31 (14.5%) Group D, 19 (9%) Groups E or G and 15 (7%) other/nonspecified. The predominant NTS pathogen was Salmonella heidelberg occurring in 37 (17.5%) cases. Forty-five percent of children were female. (Table 1) Forty-two percent of children were less than 3 years old with a steady rate after age 3. Two (0.9%) children had an underlying immunodeficiency, three (1.4%) additional with a malignancy and 16 (7.5%) with underlying non-immunosuppressing comorbidities.

Conclusion

Despite improvements in food safety, the rates of NTS bacteremia have not decreased over the last two decades. The rate of NTS was 1.4 per 100,000 children per year with the highest proportion in children less than 3 years. Two percent had underlying immunosuppressing comorbidities. Although only 10% had underlying comorbidities, this was substantially higher than the population at KPNC.

Disclosures

All authors: No reported disclosures.
1534. Polymyxin Antimicrobial Susceptibility (AST) Testing and Breakpoints for P. aeruginosa, A. baumannii, and Enterobacteriaceae: Recommendations from the United States Committee on Antimicrobial Susceptibility Testing (USCAST)
Authors: Pogue Jason M , Jones Ronald N , Bradley John S , Andes David , Bhavnani Sujata M , Dudley Michael , Flamm Robert K , Rodvold Keith A , Ambrose Paul G
Published: October 2019

Background

Polymyxins are important antimicrobial agents for the treatment of infections due to carbapenem-resistant and other multidrug-resistant organisms. Recently, the CLSI and EUCAST have set breakpoints for colistin (EUCAST and CLSI) and polymyxin B (CLSI) with slight differences in recommendations. However, there are issues unique to the polymyxin class that warrant additional guidances. Herein, we assess data related to breakpoint setting and make additional recommendations for polymyxin AST interpretive criteria.

Methods

Data sources included longitudinal (2011–2017) US surveillance reference broth microdilution (BMD) MIC distributions (128,573 isolates) for colistin and polymyxin B (PB), published data on accuracy of various AST methodologies, in vivo pharmacokinetic/pharmacodynamic (PK-PD) models, prior polymyxin guidelines and agency package insert dosing recommendations, and population PK-PD and toxicodynamic (TD) data. Epidemiological cut-off, PK-PD (and TD), and clinical data were all considered for susceptible (S) breakpoint determinations.

Results

Data demonstrate that the most commonly utilized AST methodologies (disk diffusion, Etest, and automated MIC susceptibility panels), as well as agar dilution testing cannot reliably detect resistance; and BMD is the preferred AST. Importantly, colistin S is a reliable surrogate for PB S with cross-S accuracy at > 99% of isolates in each pathogen group. Breakpoint recommendations can be found in the Table with emphasis on applying combination therapy. Key recommendations include an S breakpoint of ≤2 mg/L for each pathogen (both colistin and PB). However, based on a lack of preclinical efficacy in murine pneumonia models, PK/PD concerns, and poor clinical outcome data, we strongly suggest that no breakpoints are applied for pneumonia and that alternative therapies should be used where available. Additionally, due to a lack of significant renal excretion, PB will also have no S breakpoint recommendation for lower urinary tract infections.

Conclusion

The polymyxins have compromising characteristics that make them suboptimal antimicrobials when used alone, and additional caveats are required for AST breakpoint interpretive criteria and stewardship programs.

Disclosures

All authors: No reported disclosures.
1540. A Population Pharmacokinetic Model for Vancomycin in Korean Patients Receiving Extracorporeal Membrane Oxygenation Therapy: A Prospective Study
Authors: Jung Younghee , Lee Dong-Hwan , Soo Kim Hyoung
Published: October 2019

Background

There is no literature on population pharmacokinetics (PK) of vancomycin in Korean patients receiving extracorporeal membrane oxygenation (ECMO) therapy. The aim of this study was to develop a population PK model for vancomycin in Korean ECMO patients.

Methods

We prospectively enrolled adult patients who were undergoing ECMO and receiving vancomycin from July 2018 to April 2019. After initial dose of vancomycin was administrated, serial blood samples (seven to nine times per patient) were drawn before the next dose. A population PK model for vancomycin was developed using a nonlinear mixed-effect modeling. Age, sex, creatinine clearance, and body weight were tested as potential covariates in the model. Model selection was based on log-likelihood test, model diagnostic plots, and clinical plausibility.

Results

Fourteen patients were included over the period. Ten received venovenous, three venoarterial, and one both type ECMO. Eleven were men and the median age was 54 (interquartile range 45–66.3). Mean estimated glomerular filtration rate (eGFR) was 69 ± 46 mL/minute/1.73m2 by the modification of diet in renal disease equation. A total of 123 vancomycin concentrations from the patients were included in the analysis. The population PK of vancomycin was best described by a two-compartment model with a proportional residual error model. The typical value (%between-subject variability) for total clearance was estimated to be 4.33 L/h (21.6%), central volume of distribution was 9.22 L, the intercompartmental clearance was 10.75 L/hr (34.9%) and the peripheral volume of distribution was 19.6 L (26.6%). The proportional residual variability was 8.81%. Creatinine clearance significantly influenced vancomycin clearance (CL). The proposed equation to estimate vancomycin clearance in Korean ECMO patients was CL = 4.33 + 0.199 × (eGFR – 56).

Conclusion

A two-compartment population PK model successfully describes vancomycin PK profiles in Korean ECMO patients. The model could be used to optimize the dosing regimen if more data become available from currently ongoing clinical study.

Disclosures

All authors: No reported disclosures.
1556. Assessment of Translational In Vitro and Animal Pharmacokinetic–Pharmacodynamic Data Used to Support Drug Development of Recent Tetracycline Derivatives
Authors: Moore Jason , Pahwa Sonia , Yan Danielsen Zhixia , Colangelo Philip
Published: October 2019

Background

Nonclinical (animal and in vitro) models are commonly used during the development of antibacterial drugs. Pharmacokinetic (PK) and pharmacodynamic (PD) data obtained from these nonclinical models are used to generate a PK-PD target, which can then be bridged to humans in a probability of PK-PD target attainment (PTA) analysis to support selection of the dose regimen for phase 3 trials and in vitro susceptibility testing criteria (breakpoints) to guide clinical usage.

Methods

Two recently approved tetracycline antibacterial drugs, eravacycline (ERV) and omadacycline (OMD), were evaluated. PK-PD data from nonclinical models and clinical microbiological response were collected from each of the respective clinical pharmacology reviews and assessments published by FDA and EMA, respectively. The highest MICs (minimum inhibitory concentrations) reflecting 80% success in the ability of the drug to inhibit growth in the target bacteria were identified from clinical and nonclinical data and termed the MIC cutoff. The nonclinical MIC cutoff was obtained from the PTA analysis using the PK-PD targets from animal studies. The clinical MIC cutoff was obtained from microbiological response (microbiological intent-to-treat population) data from clinical trial experience. The ratios of the clinical and nonclinical MIC cutoffs were calculated and used to evaluate potential discrepancies between the animal model prediction and clinical trial experience.

Results

The drug development programs for ERV and OMD included murine infection models and in vitro models to characterize PK-PD. The clinical to nonclinical MIC cutoff ratios ranged from 4 to 32. Higher values of the MIC cutoff signify that the drug can treat larger proportions of the bacterial population; therefore, high clinical to nonclinical MIC cutoff ratios signify that the drugs had more activity in reducing the bacterial population in clinical than in nonclinical studies.

Conclusion

Thus, the nonclinical models for ERV and OMD under-predicted microbiological response and breakpoints. While nonclinical models are generally useful, more characterization of translational factors may be needed to allow nonclinical models to be more predictive of clinical trial outcomes.

Disclosures

All authors: No reported disclosures.
1561. Omadacycline Pharmacokinetics: Influence of Mortality Risk Score Among Patients with Community-Acquired Bacterial Pneumonia
Authors: Lakota Elizabeth A , Friedrich Lawrence , Steenbergen Judith N , McGovern Paul C , Tzanis Evan , Bhavnani Sujata M , Rubino Christopher M
Published: October 2019

Background

Omadacycline is a novel aminomethylcycline with activity against Gram-positive and -negative organisms, including tetracycline-resistant pathogens. Omadacycline was recently approved in the United States for treatment of adult patients with community-acquired bacterial pneumonia (CABP) and acute bacterial skin and skin structure infections. Analyses were undertaken to determine whether PORT risk class and CURB-65 score influence the pharmacokinetics of omadacycline in patients with CABP.

Methods

Omadacycline pharmacokinetic data were available from omadacycline-treated patients with CABP enrolled in the Phase 3 OPTIC Study. Patients received omadacycline 100 mg IV q12h on Day 1 followed by 100 mg IV q24h. After Day 3, patients could be switched to 300 mg PO q24h if predefined clinical stability criteria were met. Four pharmacokinetic samples per patient were collected between Days 2 and 5. These data were previously utilized in the development of a population pharmacokinetic model describing the disposition of omadacycline [Microbe 2018; Abstr SAT-628]. Individual post-hoc parameter estimates for patients enrolled in the OPTIC study were utilized to compute Day 1 total-drug plasma area under the concentration-time curve (AUC) values following administration of omadacycline 100 mg IV q12h. Differences among these AUC values by PORT risk class and CURB-65 score were assessed using a one-way ANOVA.

Results

A total of 187 pharmacokinetic samples were available from 50 patients. Among the patients classified as PORT risk class II, III, and IV (n = 12, 28, and 10, respectively), mean Day 1 omadacycline AUC values were 10.2, 11.0, and 12.0 mg L/h, respectively. Among patients with CURB-65 scores of 0, 1, and 2 (n = 23, 23, and 4, respectively), mean Day 1 omadacycline AUC values were 10.6, 11.6, and 9.7 mg L/h, respectively. The differences in mean AUC values were not statistically significant among patients by PORT risk class (P = 0.248) and CURB-65 score groups (P = 0.745). Moreover, variability was similar across these groups as displayed in Figure 1.

Conclusion

Omadacycline exposures were similar across PORT risk class and CURB-65 score groups; thus, omadacycline dose adjustments based on these classifications are likely not warranted.

Disclosures

All authors: No reported disclosures.
1566. Population Pharmacokinetics of Voriconazole: Serum Albumin Status as a Novel Marker of Clearance and Dosage Optimization
Authors: Chantharit Prawat , Tantasawat Montira , Kasai Hidefumi , Tanigawara Yusuke
Published: October 2019

Background

Voriconazole (VRCZ) is a first-line agent for the treatment of invasive aspergillosis. In this study, we report the first study on population pharmacokinetics (PPK) of VRCZ in Thai patients.

Methods

A PPK study was performed by combining blood VRCZ data from intensive pharmacokinetic (PK) sampling and trough concentration. A non-linear mixed-effect model with FOCE ELS optimization by Phoenix NLME was used. Validity of the model was confirmed by bootstrap, visual predictive check (VPC) and goodness-of-fit (GOF) plot. Recommended dosage regimens based on albumin level of patient were simulated.

Results

One hundred and six patients using oral VRCZ were included. Eighty-eight patients had the phenotype results which were 43, 37, and 8 of extensive metabolizer (EM), intermediate metabolizer (IM) and poor metabolizer (PM), respectively. The linear one-compartment model with first-order absorption and elimination by fixing Ka value at 1.0 well described the data. CYP2C19 phenotypes did not influence any PK parameter during the covariate model building, then all 106 patients were included in the model construction. The final model was V (Liter) = θ V × (Actual body weight/55) θ1 × exp (η V), CL (L/hr) = θ CL × (albumin/28) θ2 × (logGGT/2.4)θ3 × exp (η CL), Table 1. Estimated clearance (CL) and volume of distribution (V) values were 7.33 L hour−1and 439.69 L, respectively. VPC (Figure 1) and 96% of 1000 succeeded bootstrap results (Table1) showed a good consistency to the observed data. Serum albumin had more impact correlation across all patients with CL, R2 = 0.18, P ≤ 0.001. Patient with serum albumin 30 g/L had CL lower than patient having serum albumin > 30 g/L, P = 0.0007, irrespective of PM status because of there were all phenotypes which distributed across two groups; %EM: %IM: %PM for 55: 38.3: 6.6 and 48:36:16, respectively. Dosing simulation (Table 2) found that patient having albumin 30 g/L required a lower daily maintenance dose to achieve any trough level.

Conclusion

Serum albumin is a novel marker influencing VRCZ CL. Therapeutic drug monitoring with this dosing regimen could be another practical option for more specialized patient condition.

Disclosures

All authors: No reported disclosures.
1567. Pharmacokinetic/Pharmacodynamic Target Attainment in Adult and Pediatric Patients following Administration of Ceftaroline Fosamil as a 5-Minute Infusion
Authors: Riccobene Todd , ScD T J Carrothers, , Knebel William , Raber Susan , Chan Phylinda L S
Published: October 2019

Background

Ceftaroline fosamil is approved in the United States for treating patients ≥2 months old with acute bacterial skin and skin structure infections and community-acquired bacterial pneumonia, and for similar indications in Europe. The active metabolite, ceftaroline, has in vitro activity against common Gram-positive pathogens, including methicillin-resistant Staphylococcus aureus and Streptococcus pneumoniae. Population pharmacokinetic (popPK) modeling and simulation were used to assess systemic exposure and PK/pharmacodynamic (PK/PD) target attainment for S. aureus and S pneumoniae for 5- and 60-minute infusions.

Methods

A simultaneous popPK model, including 2 compartments each, for ceftaroline fosamil and ceftaroline was previously developed using an extensive database of adult and pediatric data. An effect of renal function maturation as a function of postmenstrual age was included on ceftaroline clearance for children <2 years. This model was used to conduct simulations for-approved ceftaroline doses administered as 5- and 60-min infusions to adult and pediatric patients with normal renal function and mild renal impairment. For adults, 100 simulations of 300 patients each were performed for each dose regimen, and covariates were generated from a multivariate normal distribution using covariate correlations from observed data. For pediatric patients, 100 simulations were performed for each dose regimen with 600 patients in each 1-month age group. Weights for pediatric age groups were based on CDC growth charts.

Results

The median proportion of simulated patients with normal renal function achieving %fT>MIC targets of 35% and 44% (associated with 1-log kill of S. aureus and S pneumoniae, respectively), are shown for 5- and 60-min infusions (figure). PK/PD target attainment was similar for both infusion times and was >99% at an MIC of 1 mg/L for S. aureus and an MIC of 0.5 mg/L for S pneumoniae. Ceftaroline AUC was similar for both infusion times, and Cmax was approximately 30%–40% higher for the 5-min infusion.

Conclusion

Ceftaroline fosamil gave as a 5-min infusion to adult and pediatric patients ≥2 months of age achieved similar PK/PD target attainment as a 60-min infusion for S. aureus and S pneumoniae for MICs up to 1 mg/L and 0.5 mg/L, respectively.

Disclosures

All authors: No reported disclosures.
1590. Updated Aminoglycoside (AG) MIC Breakpoints (BP) to Minimize Adverse Events and Improve Outcome: Impact on Susceptibility (S) Rates
Authors: Pfaller Michael A , Flamm Robert K , Ambrose Paul G , Andes David , Bradley John S , Bhavnani Sujata M , Jones Ronald N
Published: October 2019

Background

In 2016 USCAST, the National Advisory Committee (NAC) for the United States (US) to EUCAST, undertook the re-evaluation of the in vitro susceptibility (AST) test interpretive criteria (IC) for gentamicin (GM), tobramycin (TO) and amikacin (AK) against Enterobacteriaceae (ENT), P. aeruginosa (PSA) and S. aureus (SA) based on an analysis of contemporary microbiology and PK/PD data. In 2019 USCAST posted the third version (www.uscast.org) of AG IC document and CLSI and EUCAST has published AG IC in CLSI M100-S29 and EUCAST v 9.0 documents. USCAST ICs for S were generally lower than those proposed by CLSI for all organism/drug combinations. PK/PD emphasized high, extended interval dosing (5 renal function groups) to reduce nephro-vestibular toxicity and a stasis exposure endpoint. Here, we evaluate the impact on S rates for US AST data that these IC changes created.

Methods

Clinical isolates from 2010 to 2018 US SENTRY Program (reference broth microdilution AST) were analyzed for S based on current and previous IC values. AG results for GM, TO and AK were evaluated against 66,280 ENT, 13,959 PSA and 51,950 SA. Benchmark S data for meropenem, cefepime, piperacillin–tazobactam and new AG, plazomicin (PZM) were included as well as ESBL and carbapenem-resistant ENT (CRE; 805 isolates).

Results

S rates for ENT as determined by USCAST IC were reduced by 4.2/1.2/3.1% for AK/GM/TO (CLSI) and by 3.3% for AK (EUCAST); no S rate difference for GM and TO as determined by USCAST/EUCAST. For PSA, S decreased by 46.8/6.2% for AK/TO (EUCAST) and 51.6/6.2% (CLSI). S for SA vs. GM declined by only 0.2% (CLSI). No AG IC could be calculated/offered for Acinetobacter or GM X PSA or AM/TO X SA. Best S overall coverage X ESBL (99.2%) or CRE (97.2%) isolates was by PZM.

Conclusion

USCAST IC updates for AG lead to reduced values for some organism/drug combinations among ENT and PSA compared with those proposed elsewhere. The USCAST-recommended ICs were based on achieving AUC/MIC ratio target associated with net bacterial stasis. Given the assumption of AG combination therapy, stasis was considered a reasonable endpoint when evaluating AG ICs to improve both safety and efficacy. Some organism X drug exposures could not be calculated and lower IC for pneumonia isolates (GM, TO) was recommended.

Disclosures

All authors: No reported disclosures.
1598. Antimicrobial Activity of the Novel β-Lactam Enhancer Combination Cefepime–Zidebactam (WCK-5222) Tested Against Gram-Negative Bacteria Isolated in United States Medical Centers from Patients with Bloodstream Infections
Authors: Castanheira Mariana , Huband Michael D , Flamm Robert K , Sader Helio S
Published: October 2019

Background

Zidebactam (ZID) is a β-lactam enhancer antibiotic with a dual mechanism of action: high binding affinity to gram-negative PBP2 and β-lactamase (BL) inhibition. We evaluated the activity of cefepime (FEP) combined with ZID against contemporary clinical isolates of gram-negative bacilli (GNB) causing bloodstream infections (BSIs) in the US hospitals.

Methods

1,239 GNB were consecutively collected (1/patient) from 34 US medical centers in 2018. Susceptibility (S) testing against FEP-ZID (1:1 ratio) and comparators were performed by reference broth microdilution method in a central laboratory. The FEP S breakpoint of ≤ 8 mg/L (CLSI, high dose) was applied to FEP-ZID for comparison purposes. An FEP-ZID S breakpoint of ≤ 64 mg/L has been proposed for non-fermentative GNB based on pharmacokinetic/pharmacodynamic target attainment and was also applied. Selected Enterobacterales (ENT) isolates were evaluated by whole-genome sequencing.

Results

FEP-ZID was highly active against ENT (MIC50/MIC90, 0.03/0.12 mg/L; highest MIC, 4 mg/L; Table), including multidrug-resistant (MDR, MIC50/MIC90, 0.12/0.25 mg/L) and carbapenem-resistant isolates (n = 7; MIC50, 0.5 mg/L). The highest FEP-ZID MIC values among E. coli, K. pneumoniae, and E. cloacae were 1, 2, and 0.25 mg/L, respectively. The most active comparators tested against MDR ENT were ceftazidime–avibactam (CAZ-AVI; MIC50/MIC90, 0.25/1 mg/L; 98.0%S), meropenem (MEM; MIC50/MIC90, 0.03/0.12 mg/L; 93.1%S) and amikacin (AMK; MIC50/MIC90, 4/16 mg/L; 92.1%S). The most active agents tested against P. aeruginosa were FEP-ZID (MIC50/MIC90, 1/4 mg/L; highest MIC, 8 mg/L), colistin (MIC50/MIC90, 0.5/1 mg/L; 100.0%S), and AMK (MIC50/MIC90, 4/8 mg/L; 99.2%S); whereas CAZ-AVI and ceftolozane–tazobactam were active against 96.5–96.7% of isolates. FEP-ZID exhibited good activity against Acinetobacter spp. (MIC50/MIC90, 2/8 mg/L) and S. maltophilia (MIC50/MIC90, 4/32 mg/L). S. maltophilia displayed low S rates to most comparators.

Conclusion

FEP-ZID demonstrated potent activity against a large collection GNB from BSI, including isolates resistant to other BL inhibitor combinations and/or carbapenems. These results support further clinical development of FEP-ZID.

Disclosures

All authors: No reported disclosures.
1599. AUC24 Vancomycin Bayesian-Based Dosing: Increasing Therapeutic Target Attainment with Decreased TDM Cost
Authors: Sabourenkov Paul E , McLeay Robert C
Published: October 2019

Background

Vancomycin efficacy is optimally predicted by the area under the concentration–time profile (AUC24), however, traditional AUC24-based dosing methods involve analytic PK calculations that require both peak and trough drug levels, increasing cost and time compared with trough-based dosing. Recent literature (e.g., Rybak et al 2019) suggest that Bayesian dosing tools alleviate the cost and difficulty of implementing AUC24-based dosing in order to improve patient outcomes. In this study, we compare therapeutic range attainment across 5 hospitals using trough-based dosing vs. 5 hospitals using Bayesian-supported AUC24 dosing.

Methods

De-identified data were available from 5 hospitals across the United States, EU, and Australia that used a trough-based dosing method (375 adult patients, 13,024 doses, 4,654 drug levels), and from 5 hospitals that implemented Bayesian-based AUC24 dosing (370 patients, 13,080 doses, 3,520 drug levels) using commercially available software (DoseMeRx). The proportion of doses in the therapeutic target range was determined for each hospital, and the number and cost of therapeutic drug monitoring (TDM) levels required were compared.

Results

In the 5 trough-based dosing hospitals, only 49.1% of doses achieved the therapeutic target of 10–20mg/L with significant variance per-hospital in the proportion of sub- and supra-therapeutic doses (range 11–35% and 14–41% respectively). Hospitals that implemented Bayesian-based AUC24 dosing successfully attained the target AUC24 (400–700mg.h/L) for 73.5% of doses, similar to a previous AUC24-based dosing intervention using increased sampling intensity (Meng et al. 2019). The number of TDM levels used for trough-based dosing was 1 per 1.34 days compared with 1 per 2.14 days in the AUC24 group (37.4% fewer levels). Bayesian-based AUC24 dosing hospitals not only avoided increased TDM costs, but counter-intuitively had decreased cost relative to the trough-based group. At a cost of $35USD per level (Meng et al. 2019), for a 500-bed hospital, this equates to savings of $60,305 per annum.

Conclusion

This study demonstrates that implementing Bayesian-based AUC24 dosing results in improved therapeutic target attainment. TDM levels were less frequent in the Bayesian-based AUC24 dosing group, leading to decreased cost.

Disclosures

All authors: No reported disclosures.
1602. Antibiotic Resistance Patterns of Clinical Escherichia coli Urinary Isolates by Outpatient Practice Type
Authors: Frisbie Lauren , Weissman Scott , Kapoor Hema , D’Angeli Marisa A , Salm Ann , Rabinowitz Peter
Published: October 2019

Background

Antibiotic-resistant E. coli (EC) infections represent a major cause of morbidity and mortality, and pose a challenge to antibiotic stewardship. At present, clinicians in outpatient facilities may not have access to local antibiogram data to guide stewardship. Additionally, antibiotic resistance may vary between types of outpatient practices.

Methods

Using the database of a major clinical reference lab, this study analyzed several years of antibiotic susceptibility results for outpatient urinary EC isolates from Washington State. We compared rates of resistance to antibiotics between different types of outpatient practices, categorized using a modification of published ambulatory practice categories. Logistic regression was used to examine the association of outpatient practice type with antibiotic resistance, controlling year, sex, and age.

Results

After adjusting for year, sex, and age, logistic regression found significantly higher odds of resistance in urology compared with the reference groups of general family practice for ampicillin (OR 1.35), ciprofloxacin (OR 2.27), trimethoprim-sulfa (OR 1.51) and gentamicin (OR 1.73). We also saw increased odds of resistance to ciprofloxacin in patients from an oncology clinic (OR 1.56) as well as patients from “All other specialties” (OR 1.37). A lower odds of resistance was found in OBGYN clinics for ampicillin (OR 0.86), trimethoprim-sulfa (0.81) while a greater odds or resistance in OBGYN clinics was found for nitrofurantoin (OR 1.36).

Conclusion

Antibiotic resistance in EC urinary isolates can vary across types of outpatient practices according to clinical practice type. This may reflect differences in patient morbidity and/or differences in antibiotic stewardship practices and deserves further investigation. Patients with recurrent cases of resistant UTIs are generally referred to a urologist, and this was reflected in our data as there a higher odds of resistance was found in urology clinics. Similarly, we found higher odds of resistance into nitrofurantoin, a commonly prescribed antibiotic for UTIs in pregnant women, in OBGYN clinics that may reflect prescribing practices. Use of clinical data to create facility and specialty-specific antibiograms in outpatient settings may enable improved and “precise” antibiotic stewardship.

Disclosures

All authors: No reported disclosures.
1604. Response to a Cluster of Haemophilus influenzae Serotype A Cases in a Small Alaska Community, 2018
Authors: Nolen Leisha , Tiffany Amanda , DeByle Carolynn , Bruden Dana , Thompson Gail , Reasonover Alisa , Hurlburt Debbie , Mosites Emily , Simons Brenna , Klejka Joe , Castrodale Louisa , McLaughlin Joseph , Bruce Michael
Published: October 2019

Background

Between May and July 2018, four invasive cases of Haemophilus influenzae type a (Hia) occurred in a remote Alaska community. A public health response was performed to prevent further illness and to understand local Hia transmission.

Methods

The team identified close contacts of the Hia patients, collected oropharyngeal (OP) swabs and provided prophylactic rifampin. Close contacts were persons who spent ≥4 hours with a Hia patient for ≥ 5 of the 7 days preceding hospitalization. Five days later, OP swabs were collected community-wide and prophylactic rifampin was offered to community members aged <10 years. Eight weeks later, OP swabs were collected from all willing community members. Samples were tested using PCR and culture to identify Hi carriage.

Results

No Hia cases occurred in this community after the response. The pretreatment carriage prevalence is shown in Figure 1. There was a significant difference in prevalence of Hia carriage between contacts (4/27, 14.8%) and non-contacts (7/364, 1.9%) (P = 0.0043). Contacts aged <10 years were significantly more likely to carry Hia compared with contacts aged ≥10 years (11/18 [61.1%] vs. 3/34 [8.8%], P = 0.0001). The case households had the highest proportion of individuals who carried Hia at any time, with 54%–60% of individuals in three case households carrying Hia at least once. Hia carriage was eliminated in two carriers who completed treatment and were tested immediately after rifampin prophylaxis. Testing 8 weeks later found that the prevalence of carriage did not significantly change in the contacts (5/42 [11.9%] to 6/25 [24%], P = 0.18) or the non-contacts (7/368 [1.9%] to 2/114 [1.8%], P = 0.47).

Conclusion

Children aged <10 years who had close contact with the Hia patients were the most likely to carry Hia. These findings suggest that people who do not have close contact do not benefit from prophylaxis as they have very low Hia carriage. While rifampin prophylaxis eliminated carriage of Hia in the short term, carriage prevalence did not change in the long term. Further research is needed to understand why contacts have such a high prevalence of carriage even after receiving appropriate prophylactic medication.

Disclosures

All authors: No reported disclosures.
1605. Temperature Modulates the Rate of Increase of Antibiotic Resistance Across Europe
Authors: McGough Sarah , MacFadden Derek , Hattab Mohammad , Molbak Kare , Santillana Mauricio
Published: October 2019

Background

Widely recognized as a major public health threat globally, the rapid increase of antibiotic resistance in bacteria could soon render our most effective method to combat infections obsolete. Factors influencing the burden of resistance in human populations remain poorly described, though temperature is known to play an important role in mechanisms of bacterial growth and transmission.

Methods

Here, we present the first evidence that ambient temperatures may modulate the rate of increase of antibiotic resistance across Europe. Using a comprehensive dataset containing information across 28 countries, for 17 years (2000–2016), 3 common bacterial pathogens, and 4 antibiotic classes collectively representing over 4 million tested isolates, we show that antibiotic resistance has increased more rapidly in warmer regions over a period of nearly 2 decades.

Results

Specifically, we show that European countries with 10°C warmer ambient temperatures have experienced more rapid increases in antibiotic resistance to E. coli and K. pneumoniae over the 17-year period, ranging between 0.33%/year (95% CI 0.2, 0.5) and 1.2%/year (0.4, 1.9), even after accounting for recognized drivers of resistance including antibiotic consumption and population density. We found a decreasing relationship for S. aureus and methicillin of -0.4%/year (95% CI −0.7, 0.0), reflecting widespread declines in MRSA across Europe over the study period.

Conclusion

Our findings suggest that rising temperatures globally may hasten the spread of resistance and complicate efforts to mitigate it.

Disclosures

All authors: No reported disclosures.
1612. Listeriosis in Mainland China: A Systematic Review
Authors: zhangling fan , Jing Xie , Huanling Wang
Published: October 2019

Background

The aim of present study is to conduct a systematic review to better understand the epidemiological and clinical characteristics of listeriosis cases in mainland China.

Methods

The six most widely used Chinese and English databases were searched. Records on cases of listeriosis in mainland China reported from 2011 to 2017 were extracted. Clinical data of patients and information on clinical isolates of Listeria were collected and analyzed.

Results

A total of 136 records and 562 listeriosis cases were reported. The number of cases was much higher than that reported in the past decade. The 227 included non-perinatal listeriosis cases had a mortality rate of 23.78%. Of the 231 perinatal listeriosis cases, 32.68% resulted in abortion and/or newborn death. All listeriosis cases were reported as sporadic cases. Only 3 cases were traced to a meat product, while 33.12% were healthcare-associated cases.

Conclusion

The number of listeriosis cases in China may have previously been underestimated. Perinatal cases in mainland China took a much higher proportion compared with what is usually described. Considering the high number of listeriosis patients in China, a comprehensive monitoring system for listeria is urgently needed in China.

Disclosures

All authors: No reported disclosures.
1621. Acute Cardiovascular Events Among Adults Hospitalized with Influenza, FluSurv-NET, 2010–2018
Authors: Chow Eric J , Rolfes Melissa A , O’Halloran Alissa , Anderson Evan J , Bennett Nancy M , Billing Laurie M , Chai Shua , Dufort Elizabeth , Kim Sue , Irizarry Lourdes , Lynfield Ruth , Monroe Maya , Risk Ilene , Stephens Samantha , Talbot Keipp , Thomas Ann , Yousey-Hindes Kim , Reed Carrie , Garg Shikha
Published: October 2019

Background

Influenza virus infection most commonly causes acute respiratory tract illness, however may also lead to non-respiratory complications including acute cardiovascular (CV) events. We describe the frequency of and risk factors for acute CV events in adults hospitalized with influenza in the United States.

Methods

We included adults aged > 18 years hospitalized during influenza seasons 2010–2011 through 2017–2018 in FluSurv-NET, a multi-state population-based surveillance system that includes detailed medical chart review of patients hospitalized with laboratory-confirmed influenza. We defined acute CV events by International Classification of Diseases (ICD) primary and secondary discharge diagnosis codes for acute heart failure (aHF), acute ischemic heart disease (aIHD), hypertensive crisis, cardiogenic shock, acute myocarditis, acute pericarditis and cardiac tamponade. We calculated the frequency of acute CV events and used multivariable logistic regression among the 87% treated with influenza antivirals to identify independent factors associated with aHF and aIHD, the two most common diagnoses.

Results

Of 80,374 adults hospitalized with laboratory-confirmed influenza, 12% had > 1 acute CV event. We found that aHF (46%) and aIHD (42%) were the most common, followed by hypertensive crisis (8%), cardiogenic shock (3%), acute myocarditis (0.7%), acute pericarditis (0.4%) and cardiac tamponade (0.2%). Compared with treated patients without an acute cardiovascular event, treated patients with aHF (Figure A) and aIHD (Figure B) were more likely to be older, currently/formerly use tobacco and have underlying conditions including cardiovascular disease, diabetes mellitus, and kidney disease.

Conclusion

Among adults hospitalized with laboratory-confirmed influenza, acute CV events are common, particularly among those with prior cardiovascular disease. During the influenza season, clinicians should consider influenza virus infection in hospitalized adults who present with acute CV events. Non-respiratory complications, specifically aHF and aIHD, may be an under-recognized contributor to the burden of influenza.

Disclosures

All authors: No reported disclosures.