bluuebunny/crossref_metadata_2025_split huggingface dataset:
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

Abstract

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

Abstract

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

Abstract

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

Abstract

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

Abstract

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

Abstract

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

Abstract

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

Abstract

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

Abstract

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

Abstract

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.