bluuebunny/crossref_metadata_2025 huggingface dataset:
1542. The Evaluation of the In Vitro Synergy of Colistin in Combination with Meropenem and Tigecycline against 50 Multi-Drug-resistant Acinetobacter baumannii strains
Authors: Abdul-Mutakabbir Jacinda , Yim Juwom , Nguyen Logan , Kebriaei Razieh , Stamper Kyle , Maassen Philip , Kaye Keith S , Rybak Michael J
Published: October 2019

Background

Acinetobacter baumannii possess inherent and acquired antibiotic resistance mechanisms that have rendered most antibiotics, including carbapenems, inactive. Colistin (COL) has risen as salvage therapy against these organisms due to its retained activity against A. baumannii. However, COL monotherapy is often met with suboptimal outcomes. Recently, combination therapy with COL and meropenem (MEM) or tigecycline (TGC) has been shown to be effective in eradicating multi-drug-resistant A. baumannii infections. The objective of this study was to further evaluate the efficacy of COL in combination with MEM or TGC against 50 multi-drug-resistant A. baumannii strains.

Methods

Fifty carbapenem-resistant A. baumannii strains were evaluated using combination minimum inhibitory concentration (MIC) testing and time-kill analysis (TKA). Single-drug MIC testing was performed for each strain by broth microdilution. Combination MIC testing was performed for COL+MEM and COL+TGC. Each strain was evaluated via 24-hour TKA to assess the synergistic capabilities of COL+MEM, and COL+TGC. Synergy was defined as a ≥ 2-log reduction CFU/mL in either combination from the most active single agent, while bactericidal activity was defined as a ≥ 3-log reduction CFU/mL of either combination from the initial inoculum.

Results

All 50 strains were resistant to MEM and TGC with MICs ≥ 64 µg/mL and ≥ 4 µg/mL respectively; while 3 strains were resistant to COL, MICs ≥ 2 µg/mL. MEM and TGC MIC values were reduced as much as 128-fold (median 2-fold) and 32-fold (median 2-fold),, respectively, in the presence of subinhibitory COL. COL MIC values were reduced as much as 512-fold (median 4-fold) from baseline in the presence of subinhibitory MEM, and as high as 16-fold (median 2-fold) in the presence of TGC. In TKAs, COL+MEM was synergistic in 45/50 (90%) strains and bactericidal against 43/50 (86%) strains. COL+TGC TKAs revealed synergy in 32/50 (64%) strains, and bactericidal activity against 28/50 (56%) strains.

Conclusion

The combinations of COL+MEM and COL+TGC demonstrate promise in combating highly resistant A. baumannii. Further research is mandated to explore other combinations that are capable of eradicating multi-drug-resistant A. baumannii.

Disclosures

All authors: No reported disclosures.
1543. Ceftaroline Model-based Dose Individualization in an Infant with Kidney Disease and Mediastinitis
Authors: Murphy Mark , Tang-Girdwood Sonya , Tang Peter , Rebecca Brady C , Mizuno Tomoyuki , Vinks Alexander
Published: October 2019

Background

Options for the treatment of infections caused by resistant gram-positive bacteria are limited in children with kidney disease. Ceftaroline (CFD) may be an attractive option but dosing recommendations are not available for children with renal dysfunction. We present a case of pharmacokinetics (PK) model-based individualization of CFD in an infant with kidney disease and mediastinitis. A 5-week-old infant with a hypoplastic left side of the heart developed mediastinitis following a Norwood and BT shunt. Blood and chest washout cultures grew S. epidermidis. Vancomycin therapy led to acute kidney injury (AKI) (eGFR ~15mL/minute) and therefore, CFD was initiated at 8 mg/kg every 12 hours. The model-based clinical service was consulted to assist with dosing.

Methods

Plasma levels were drawn on day 2 and 10 of CFD. CFD concentrations were determined by HPLC. The pharmacodynamic (PD) target used the MIC of the isolate, 1 µg/mL, and assumed drug diffusion into the mediastinum at 20% of plasma. The PD target was ƒT>MIC at 100%. Individual PK parameters were estimated using Bayesian estimation with MWPharm++ (Mediware, the Netherlands).

Results

CFD dosing of 8 mg/kg every 12 hours resulted in concentrations well above the target. The trough level was 10 times higher than levels seen in clinical trials. Repeat levels were checked on day 10 due to improved renal function (eGFR 30 mL/minute) and changes in volume status. Changes in both clearance and volume were noted. ƒT>MIC was maintained 100% during dosing intervals. We dose optimized CFD to achieve the target while minimizing potential toxicity with long-term use. A new dosing regimen, 5.4 mg/kg every 8 hours, was started on day 12 and continued for 6 weeks.

Conclusion

This is the first case report of CFD use in a child with AKI. Though initial dosing resulted in high concentrations, no adverse effects were noted. Successful treatment was completed with a final dosing regimen of 5.3 mg/kg every 8 hours, below the recommended 8 mg/kg every 8 hours. Lower dosing was needed to decrease high drug exposure due to the decreased clearance. This case also demonstrated the feasibility of PK model-based precision dosing within 48 hours, and documented utility in the setting of changes in renal function. Further PK/PD studies are needed in children with renal dysfunction.

Disclosures

All authors: No reported disclosures.
1552. Correlation Between Vancomycin Serum Trough Concentrations and Area Under the Curve in Pediatric Patients
Authors: Weaver Krista , Kumar Madan , Nelson Allison , Bhagat Palak
Published: October 2019

Background

Despite years of experience with vancomycin (VAN), the optimal method to monitor VAN therapy in pediatric patients is still unknown. Recent pediatric data indicate serum trough concentrations lower than 10–20 mg/L or 15–20 mg/L based on indication may achieve an AUC24> 400 mg hours/L. The primary study objective was to compare AUC24 to goal VAN serum trough concentrations (STC).

Methods

A retrospective chart review of pediatric patients who received intravenous VAN June 1, 2018 to December 31, 2018 was completed. AUC24 was calculated using a trapezoidal method with 2 steady-state serum concentrations. A serum peak concentration was drawn 1 hour and 15 minutes following the end of infusion and an STC was drawn 30 minutes prior to infusion.

Results

During 25 admissions, 12 patients had a first AUC24 at goal and 13 patients had a first AUC24 below goal. Of 41 AUC24 calculations, 27 AUC24s were ≥400 mg hours/L (group 1), and 14 AUC24s were <400 mg hours/L (group 2). Median AUC24 was 561 mg hours/L for group 1 vs. 344.5 mg hours/L for group 2 (P < 0.001). Correlating Cmin and Ctrough (Ctr) for group 1 and group 2 were 12 mg/L and 13.5 mg/L vs. 6.4 mg/L and 7.3 mg/L, respectively (P < 0.001). Figure 1 shows the pharmacokinetic parameters for each group. Spearman correlation between AUC24 and Cmin was 0.87. Of the 35 subtherapeutic VAN STCs, 20 (57.1%) achieved an AUC24 ≥400 mg hours/L (P = 0.08). Subgroup analysis of AUC24 400–600 mg hours/L showed a median AUC24 of 519 mg hours/L with correlating Cmin and Ctr of 10.6 mg/L and 11.9 mg/L, respectively. The MIC was <1 in 90.9% of cases (Figure 2). The mean VAN dose required to achieve an AUC24 ≥400 mg hours/L was 77.7 mg/kg/day; dosing frequency did not appear to affect AUC24 outcome. Time to culture clearance was 2 days in group 1 and 6.5 days in group 2 (P = 0.24). No cases of nephrotoxicity were identified despite AUC24 values ranging from 265–1294 mg hours/L.

Conclusion

AUC24 monitoring using a 2-sample trapezoidal method was successfully implemented at this institution. The results of this study align with previous pediatric studies, supporting the use of lower serum trough concentration goals of 10–15 mg/L.

Disclosures

All authors: No reported disclosures.
1553. Human-Simulated Pharmacokinetic Profiles of Cefiderocol and Meropenem Are Conserved in Murine Models of Thigh Infection With or Without Iron Overload
Authors: Kidd James M , Abdelraouf Kamilia , Nicolau David P
Published: October 2019

Background

A translational murine model of thigh infection with comorbid iron overload was previously developed to study the efficacy of iron-dependent siderophore-antibiotic conjugates under conditions where the hypoferremic response of innate immunity may be compromised. Given the potential for functional organ damage from excessive tissue iron, which could alter the pharmacokinetic (PK) profiles of antibiotics being compared for efficacy using this model, the effects of iron overload on a siderophore-β-lactam conjugate, cefiderocol (CFDC), and a non-siderophore β-lactam, meropenem (MEM), were studied.

Methods

Female CD-1 mice received iron dextran (Fe-D) 100 mg/kg intraperitoneally for 14 days as previously shown to produce vastly supranormal iron concentrations in serum, liver, and spleen (ASM Microbe 2019 abstract HMB-373). Age-matched control mice were not dosed with Fe-D. Mice were rendered neutropenic. On day 15, both thighs of iron-overloaded and control mice were inoculated intramuscularly with Acinetobacter baumannii suspensions of 107 CFU/mL. Two hours after inoculation, mice in each model were dosed with previously developed human-simulated regimens (HSR) of CFDC or MEM simulating human PK profiles after doses of 2g q8h (3 hours infusion) for both drugs. At 4 time points per regimen, 6 mice per model were sacrificed for blood collection. Plasma total MEM and CFDC concentrations were measured with HPLC and LC-MS-MS, respectively. Free concentrations were calculated with murine protein binding. At each time point, mean free concentrations in both models were compared using Student’s t-test.

Results

Observed murine-free plasma concentrations ± 95% CI of CFDC and MEM are overlaid with simulated human and murine profiles in the figure. In both models, these regimens approximated human exposures after clinical doses. For all time points and both drugs, concentrations were not significantly different (P > 0.05) between models with or without iron overload.

Conclusion

Iron overload did not significantly alter PK profiles of a siderophore-β-lactam conjugate, CFDC, or a non-siderophore β-lactam, MEM. These data support the use of CFDC and MEM HSR for pharmacodynamic studies utilizing both iron-overloaded and standard murine thigh infection models.

Disclosures

All authors: No reported disclosures.
1571. Evaluation of a Single Post First Dose Vancomycin Level to Achieve a Goal Vancomycin AUC
Authors: Hurley Evan , Ebert Steven C
Published: October 2019

Background

The 24-hour area under the serum concentration–time curve (AUC24) is the most defensible measure to predict the effectiveness and toxicity of vancomycin. The optimal method and time point to assess and optimize AUC24, however, have yet to be determined. Measuring a trough concentration at steady state has been the traditional method of monitoring vancomycin, but trough is unreliable at estimating AUC24. More accurate methods for estimating AUC24 are paired sample analysis, or a single optimally timed sample combined with population pharmacokinetics. We wished to optimize AUC24 prior to steady state for earlier goal attainment, thereby decreasing risk of treatment failure, resistance, and/or nephrotoxicity. A single optimally timed single post first dose level may be used to estimate drug clearance and thereby AUC. Based on the post first dose concentration and a population pharmacokinetic model, clearance is calculated, and the dosing regimen can be adjusted to achieve a desired AUC24. Our institution has enabled pharmacists to obtain post first dose vancomycin levels and make early dose adjustments. The aim of this project is to monitor the accuracy of this method and the outcomes of patients who have received post first dose vancomycin levels and subsequent dose assessment/adjustment.

Methods

Single-center cohort study via electronic chart review of patients with vancomycin therapeutic dose monitoring based on post first dose vancomycin levels obtained between January 2019 and April 2019.

Results

41 patients were dosed and monitored based on post first dose vancomycin levels. Fourteen patients (34%) required dose adjustments based on the post first dose level. Accuracy of assessment was determined in 15 patients (37%) via a steady-state level used to measure vancomycin clearance and AUC24. At steady-state following dose assessment 14/15 (93%) patients had desired targeted goal AUC24. Only two patients (5%) had greater than a 50% increase in baseline serum creatinine.

Conclusion

Post first dose-level analysis resulted in dose regimen modifications in one-third of patients. This consistently allowed the attainment of goal AUC24 at steady-state.

Disclosures

All authors: No reported disclosures.
1573. Population Pharmacokinetic Analyses for Cefepime in Adult and Pediatric Patients
Authors: Liu Jiajun , Neely Michael , Lipman Jeffrey , Sime Fekade B , Roberts Jason , Kiel Patrick J , Scheetz Marc H
Published: October 2019

Background

Cefepime (CEF) is commonly used for adult and pediatric infections. Several studies have examined CEF’s pharmacokinetics (PK) in various populations; however, a unifying PK model for adult and pediatric subjects does not yet exist. We developed a combined population model for adult and pediatric patients and validated the model.

Methods

The initial model includes adult and pediatric patients with a rich cefepime sampling design. All adults received 2 g CEF while pediatric subjects received a mean of 49 (SD 5) mg/kg. One- and two-compartment models were considered as base models and were fit using a non-parametric adaptive grid algorithm within the Pmetrics package 1.5.2 (Los Angeles, CA) for R 3.5.1. Compartmental model selection was based on Akaike information criteria (AIC). Covariate relationships with PK parameters were visually inspected and mathematically assessed. Predictive performance was evaluated using bias and imprecision of the population and individual prediction models. External validation was conducted using a separate adult cohort.

Results

A total of 45 subjects (n = 9 adults; n = 36 pediatrics) were included in the initial PK model build and 12 subjects in the external validation cohort. Overall, the data were best described using a two-compartment model with volume of distribution (V) normalized to total body weight (TBW/70 kg) and an allometric scaled elimination rate constant (Ke) for pediatric subjects (AIC = 4,138.36). Final model observed vs. predicted plots demonstrated good fit (population R2 = 0.87, individual R2 = 0.97, Figure 1a and b). For the final model, the population median parameter values (95% credibility interval) were V0 (total volume of distribution), 11.7 L (10.2–14.6); Ke for adult, 0.66 hour−1 (0.38–0.78), Ke for pediatrics, 0.82 hour−1 (0.64–0.85), KCP (rate constant from central to peripheral compartment), 1.4 hour−1 (1.3–1.8), KPC (rate constant from peripheral to central compartment), 1.6 hour−1 (1.2–1.8). The validation cohort has 12 subjects, and the final model fit the data well (individual R2 = 0.75).

Conclusion

In this diverse group of adult and pediatrics, a two-compartment model described CEF PK well and was externally validated with a unique cohort. This model can serve as a population prior for real-time PK software algorithms.

Disclosures

All authors: No reported disclosures.
1577. Particle Characterization of Nebulized Liposomal Amphotericin B and Its Use in the Treatment of Murine Pulmonary Aspergillosis
Authors: Dave Janam J , Sandoval Adilene , Olson Jon , Adler-Moore Jill
Published: October 2019

Background

Immunocompromised patients are very susceptible to pulmonary aspergillosis causing 50% mortality with present treatments, indicating a need for improved therapy. To address this, we standardized a nebulization method for effectively delivering liposomal amphotericin B (AmBisome®, AmBi) into lungs of Aspergillus fumigatus-infected mice.

Methods

AmBi particle characterization was done with a Cascade particle impactor and a Schuco S5000 nebulizer containing 1.33 mg/mL AmBi. For in vivo studies, AmBi was nebulized (neb) into a 12 compartment chamber (one mouse/compartment), following immunosuppression with 28 mg/kg triamcinolone IP (d-3, -1, +1). Mice were challenged d0 with 9 x 106A. fumigatus (ATCC#13073) and 4 hours post-challenge, divided into 5 groups (n = 12/gp): 5 days of 20 min/day neb AmBi (Gp1), 5 days of 10 min/day neb AmBi (Gp2), 20 min/day neb AmBi days 0, 1, 3, 5, 7 (Gp 3), 5 days of intravenous(IV) AmBi 7.5 mg/kg/day (Gp4) and IV PBS (Gp5). Seven mice/gp were monitored for survival to d21 and lungs, livers, kidneys, spleens (5 mice/gp) analyzed for mean amphotericin B µg/g and CFU/g.

Results

87% of neb AmBi particles were between 0.43 mm to 3.3 mm allowing for drug penetration into 1°, 2° and terminal bronchi, bronchioles, and alveoli. This resulted in very good protection, with 20 min daily neb treatments (Gp1) giving 100% survival and 10 min daily neb treatments producing 71% survival (Gp2). There were no survivors in the PBS gp (P < 0.02 vs. Gp1 and Gp2). Every other day neb AmBi or daily IV AmBi was less effective (43% survival). In addition, neb AmBi for 20 min (Gp1) yielded significantly lower fungal burden in lungs vs. all other AmBi treatments (P < 0.02). While drug was detected in lungs of mice given 20 min of neb AmBi (2.6 µg/g), there was no drug detected in livers, kidneys or spleens of any mice given neb AmBi. In comparison, with IV AmBi, drug was detected in the lungs (7 µg/g), livers (204 µg/g), kidneys (38 µg/g), and spleens (114 µg/g).

Conclusion

Daily AmBi nebulization was an effective and potentially less nephrotoxic treatment for murine pulmonary aspergillosis since it achieved significantly lower tissue fungal burden and much better survival vs. daily IV AmBi, without delivering drug to the kidneys.

Disclosures

All authors: No reported disclosures.
1581. Comparative In Vitro Activity of Ceftolozane/tazobactam and Comparator Agents Against Enterobacteriaceae and Pseudomonas Aeruginosa Clinical Isolates in Colombia
Authors: Hernández-Gómez Cristhian , De La Cadena Elsa , Mojica Maria F , Correa Adriana , Perengüez Marcela , Gutiérrez Sergio , Pallares Christian , López Catalina , Maria. Rojas Rojas Monica , Virginia Villegas Maria
Published: October 2019

Background

Multidrug-resistant Enterobacteriaceae (Ent) and Pseudomonas aeruginosa (Pae) are involved in a considerable number of healthcare-associated infections, thus representing a therapeutic challenge. Ceftolozane–tazobactam (C/T) is a combination of a novel cephalosporin with a known β-lactamase inhibitor. Ceftolozane has high affinity for penicillin-binding proteins, improved outer membrane permeability, increased stability against efflux and enhanced stability against chromosomal AmpC β-lactamases compared with other β-lactam antibiotics. This agent is not active against carbapenemases. We evaluated the in vitro activity of C/T against clinical isolates of Ent and Pae collected from 2016- 2017 and compared it to the activity of broad-spectrum antimicrobial agents.

Methods

1.644 Ent and Pae non-duplicate clinical isolates were collected in 13 medical centers located in 12 Colombian cities. Minimum inhibitory concentrations (MIC) were performed by broth microdilution and interpreted according to current CLSI guidelines. Isolates tested included 813 Escherichia coli (Eco), 441 Klebsiella pneumoniae (Kpn), 82 Enterobacter spp., (Enb); 60 Serratia marcescens (Sma) and 248 Pae. Comparator agents were ceftriaxone (CRO), cefotaxime (CTX), ceftazidime (CAZ), cefepime (FEP), piperacillin/tazobactam (TZP), ertapenem (ETP), imipenem (IMI), meropenem (MEM).

Results

Susceptibilities to C/T and comparators of 4 Ent species and Pae are shown in Table 1. Compared with other β-lactams such as CRO, CAZ, TZP, and FEP, C/T had considerably higher susceptibility rates against ESBL, non-carbapenem-resistant (CR) Eco and Kpn isolates. C/T MIC50/90 were: Eco (≤1/≤1); Kpn (≤1/128); Enb (≤1/64); Sma (≤1/≥256); Pae (≤1/≥256). In the case of P.aeruginosa despite the high resistance rates observed in the study, C/T had the best susceptibility, even higher than the carbapenems.

Conclusion

Overall, C/T demonstrated higher in vitro activity than currently available cephalosporins and TZP when tested against Ent and Pae. C/T provides an important treatment option against infections caused by non-carbapenemase producing Gram-negative pathogens. Further studies are warranted to identify an emerging mechanism of resistance in Colombia.

Disclosures

All authors: No reported disclosures.
1587. Comparative In Vitro Antipseudomonal Activity of Ceftolozane/Tazobactam Against Pseudomonas aeruginosa Isolates from Children with Cystic Fibrosis
Authors: Kanwar Neena , Harrison Christopher J , Pence Morgan , Selvarangan Rangaraj
Published: October 2019

Background

Ceftolozane/tazobactam (C/T) is a relatively new antipseudomonal cephalosporin combined with a β-lactamase inhibitor approved by the FDA in 2014. The study goal was to evaluate its in vitro activity vs. comparator agents against a pre-selected panel of Pseudomonas isolates obtained from pediatric patients with cystic fibrosis.

Methods

Clinical Pseudomonas isolates from 2 free-standing pediatric centers were obtained from respiratory samples from patients with cystic fibrosis during 2015–2017. Stored isolates were cultured on blood agar (Thermo Fisher Scientific) at 35±1°C for 18–24 hours. A 0.5 McFarland suspension was prepared with Sensititre® demineralized water. Final inocula of 5 × 10E5 CFU/mL were prepared in Sensititre® Mueller–Hinton broth. Custom-prepared Sensititre® MIC plates (Thermo Fisher Scientific) containing C/T and 10 comparator antimicrobials were inoculated and incubated at 35±1°C for 18–24 hours. MICs were determined via Sensititre Vizion® system. MIC endpoints (susceptibilities) were interpreted by CLSI (2018) breakpoint criteria.

Results

Data from 83 unique isolates from 2 sites (Missouri: 38 and Texas: 45) for the years 2015–2017 are reported. Overall, 90% of the tested isolates were C/T susceptible (MIC ≤4 μg/mL), while susceptibility for colistin, meropenem, and ciprofloxacin were 93%, 88%, and 86%, respectively (Table 1). C/T exhibited high overall activity (MIC50/90, 1/4 μg/mL) against these Pseudomonas isolates. C/T was more active than amikacin, aztreonam, cefepime, ceftazidime, ciprofloxacin, gentamycin, meropenem, piperacillin–tazobactam and tobramycin against tested Pseudomonas isolates but less active than colistin.

Conclusion

C/T had broad-spectrum activity and high potency against most Pseudomonas aeruginosa from 2 geographically diverse pediatric US medical centers.

Disclosures

All authors: No reported disclosures.
1588. Delafloxacin Activity Against Staphylococcus aureus with Reduced Susceptibility or Resistance to Methicillin, Vancomycin, Daptomycin, or Linezolid
Authors: Saravolatz Louis D , Pawlak Joan
Published: October 2019

Background

Delafloxacin is a recently approved anionic fluoroquinolone antibiotic with broad-spectrum activity against Gram-positive and Gram-negative organisms. The drug has been approved for patients with acute bacterial skin and skin structure infections including those caused by methicillin-resistant S. aureus. There is limited data available against methicillin-resistant S. aureus blood isolates (MRSABI), vancomycin intermediate strains (VISA), vancomycin-resistant strains (VRSA), daptomycin non-susceptible strains (DNSSA) and linezolid-resistant S. aureus (LRSA).

Methods

Antimicrobial activity of delafloxacin, levofloxacin, vancomycin, daptomycin, ceftaroline, and linezolid was determined against recent (2016–2018) MRSABI (110), VRSA (15), VISA (35), DNSSA (40), and LRSA (6). Broth microdilution testing using Mueller–Hinton broth was used to determine minimal inhibitory concentration (MIC) and minimal bactericidal concentration (MBC) according to CLSI guidelines. FDA breakpoints were used to determine delafloxacin susceptibility, and CLSI breakpoints were used for all other antibiotics.

Results

Antimicrobial MIC90 expressed in mg/L and (% susceptible)

None of the LRSA were susceptible to delafloxacin or levofloxacin. All strains that were susceptible to the antimicrobial agents above had an MBC that was the same as the MIC or one dilution greater except for linezolid which demonstrated an MBC that was more than eight-fold greater than the MIC. For MRSABI isolates with a levofloxacin MIC ≥ 8 mg/L (55/110) suggesting multiple mutations in the quinolone-resistant determining region, the delafloxacin MIC90 was 1 mg/L with a 36.4% susceptibility rate.

Conclusion

Delafloxacin demonstrates superior activity to levofloxacin against recent MRSA blood isolates, VISA, VRSA, and DNSSA.

Disclosures

All authors: No reported disclosures.
1591. Updated Fluoroquinolone MIC Breakpoints: Impact on Susceptibility Rates in the United States
Authors: Flamm Robert K , Pfaller Michael A , Ambrose Paul G , Andes David , Bradley John S , Bhavnani Sujata M , Jones Ronald N
Published: October 2019

Background

In 2015 USCAST, the National Advisory Committee for the United States (US) to EUCAST, produced a report (Version 1.0) on their website (www.uscast.org) re-evaluating fluoroquinolone (FQ) breakpoint interpretive criteria (IC) based on analysis of current microbiology and pharmacokinetic/pharmacodynamic (PK/PD) data. EUCAST initiated a consultative process using USCAST analyses in an effort to update FQ IC, released in 2017. CLSI formed an ad-hoc working group in late 2015 to review the USCAST FQ document and formulate questions about content. In 2018, USCAST released V1.3 of the FQ document and CLSI subsequently published updated FQ MIC IC in the M100-S29 (2019) document. This study evaluated the impact on susceptibility (S) rates for US surveillance data that these IC changes created.

Methods

Clinical isolates (reference broth microdilution MIC) from 2016–2018 US SENTRY Program were analyzed for S based on current and previous IC. FQ results for ciprofloxacin (CIP), levofloxacin (LEV), and moxifloxacin (MOX) were evaluated. Benchmark S comparison data for meropenem, cefepime, piperacillin–tazobactam and delafloxacin (new FQ) were also included.

Results

S rates for Enterobacteriaceae (ENT;Figure) were reduced by 3.8/3.7% for CIP/LEV (CLSI) and 2.3/2.5% (EUCAST). MOX-S rate vs. ENT declined 5.7% (EUCAST). Although reductions in S occurred for most organism groups, K. pneumoniae (6.0/5.5% for CIP/LEV [CLSI] and 4.0/4.2% [EUCAST]) and S. marcescens (7.4/4.1% for CIP/LEV [CLSI] and 4.1/5.0% [EUCAST]) reductions were among the largest changes. For Pseudomonas aeruginosa (PSA), CIP-S decreased 6.8% and LEV-S 10.1% (CLSI); but potential for false-S results remain using CLSI IC (5 pathogens).

Conclusion

USCAST’s comprehensive analyses of FQ IC in 2015 led to revised breakpoints for most organism/drug combinations among ENT and PSA compared with those being used before. USCAST analysis was most influenced by PK/PD in vivo data as current clinical outcomes data by MIC was limited. Awareness and interactions (both formal and informal) among breakpoint setting organizations has modified FQ ICs which are lower than previously recommended, and although not perfectly harmonized in time and detail, this represents a successful model.

Disclosures

All authors: No reported disclosures.
1601. Evaluation of Synergy with β-Lactams Plus Aztreonam Against Pseudomonas aeruginosa (PSA)
Authors: O’Donnell J Nicholas , Alnasser Donia , Maring Brittney L , Lodise Thomas
Published: October 2019

Background

Combination therapy is often employed in the treatment of PSA infections. Agents commonly used in combination with β-lactams include aminoglycosides, polymyxins, and fluoroquinolones but are limited by resistance and toxicity concerns. The use of dual β-lactam therapy is an emerging area of interest for the treatment of patients with resistant Gram-negative pathogens. This study evaluated synergy between β-lactam agents and aztreonam (ATM) against PSA isolates with varying degrees of susceptibility.

Methods

4 PSA clinical isolates were collected from Albany Medical Center; 1 ATCC isolate was used (Table 1). Synergy with cefepime (FEP), meropenem (MER), and ceftazidime (CAZ), each in combination with ATM, was assessed using fractional inhibitory concentration index determined by checkerboard method. Synergistic combinations were tested in 24-hour time-kill, utilizing minimum and steady-state physiological concentrations (Cmin and Css). Tested bacteria were grown to late log phase, diluted to 1 × 106 cfu/mL and incubated at 37°C for 24 hours. Samples were drawn at 0, 2, 4, 6 and 24 hours. Synergy in time-kill was defined as ≥ 2 log10 cfu/mL kill greater than the most active individual agent at 24 hours.

Results

In checkerboard studies, combinations with ATM resulted in 80% synergy with FEP and 60% synergy with MER or CAZ combinations. ATM/MER and ATM/CAZ time-kill experiments resulted in indifference for most organisms and concentrations tested. For both single and combination regimens, initial killing was observed but varying degrees of regrowth occurred by 24 hours. The only strain with no regrowth at 24 hours was AMC-PSA2 (bactericidal activity and no regrowth at 24 hours observed for MER Cmin MER Css, and MER+ATM Css). Against AMC-PSA2, CAZ+ATM at Cmin was synergistic with limited regrowth observed.

Conclusion

Against PSA, tested β-lactam combinations with ATM resulted in lack of synergy in time-kill experiments, despite checkerboard results. Due to the extent of regrowth observed with nearly all single agent and combination regimens, testing of alternative combinations, including those that evade common resistance mechanisms such as efflux pumps or β-lactamases, and studies of dynamic concentrations are warranted.

Disclosures

All authors: No reported disclosures.
1611. Interventions to Decrease the Absolute Number of Individuals Not Immune to Measles at Princeton University (PU)
Authors: Daskalaki Irini , Maestripieri Robin , Ganesan Gayathri , Pletcher Jonathan
Published: October 2019

Background

PU’s dormitories house ~100% of undergraduate and ~70% of graduate students. MMR is required for all students by NJ law, allowing for medical and religious exemptions (RE). Information on immunization requirements is widely available and accessible. If a student is found not compliant, measures include monetary fines, class registration holds, and contact by residential staff. Visiting short-term students should submit immunization records, but, due to rolling matriculation dates, enforcement measures may not be applicable. In the fall of 2018, a measles outbreak was reported close to campus. We sought to engage all students not immune to measles with proactive messaging.

Methods

Starting on December 3, 2018, the electronic health record (EHR) was used to generate a weekly report of active students not immune to measles following the CDC’s immunity criteria. Notifications and education material were sent via secure messaging and/or email. Students with no immunization data were provided instructions on record submission. Reminders were sent to those due for second MMR. Students with RE were offered blood tests for measles immunity. Alerts were placed in the EHR of all non-immune students so every encounter would serve as reminder. Student travelers on PU sponsored trips were informed about measles outbreaks and, often, MMR became a trip requirement.

Results

On December 3, 2018, 84 students were measles non-immune: 2 with medical and 23 with RE; 59 lacking second MMR or with no immunization data.The 23 RE became 24 when a student in absentia returned. Since, 3 of the students with RE had blood tests revealing measles immunity; 2 received MMR to travel; 3 decided that their RE was not current. On 4/22/19, there were 18 students lacking second MMR or with no immunization data, most of them new visiting students. Overall, 57% reduction of absolute number of measles nonimmune students.

Conclusion

This community intervention shows that students who remained measles non-immune despite the regular immunization compliance activities, could become compliant through active messaging, education and continued engagement. Importantly, 8 of 24 students with RE, when engaged and provided with information and potential consequences of unimmunized status, were found either already immunized or not opposed to receiving immunizations.

Disclosures

All authors: No reported disclosures.
1631. Association Between Type-Specific Influenza Circulation and Incidence of Severe Laboratory-confirmed Cases; Which Subtype Is the Most Virulent?
Authors: Lytras Theodore , Andreopoulou Anastasia , Mouratidou Elisavet , Gkolfinopoulou Kassiani , Tsiodras Sotirios
Published: October 2019

Background

Excess population mortality during winter is most often associated with influenza A(H3N2), particularly “pneumonia and influenza” deaths. We examined differences between influenza types in their association with severe laboratory-confirmed cases, to determine which is the most virulent.

Methods

We used nine seasons of comprehensive nationwide surveillance data from Greece (from 2010/11 to 2018/19) to examine the association, separately for influenza A(H1N1)pdm09, A(H3N2) and B, between the number of laboratory-confirmed severe cases (intensive care hospitalizations or deaths) and the overall type-specific circulation during the season (expressed as a cumulated incidence proxy—ILI rate times percent positive, summed over the season), using additive Poisson regression.

Results

During the study period, and for the same level of circulation during a season, influenza A(H1N1)pdm09 was associated with 3.7 times (95% CI 2.7–5.0) more laboratory-confirmed deaths compared with influenza B, and 2.2 times (95% CI 1.6–3.1) more compared with A(H3N2) (Figure 1). Similar differences were observed for intensive care hospitalizations. Laboratory-confirmed A(H1N1)pdm09 severe cases were more often younger (median age 56 years) compared with influenza B or A(H3N2) (median age 64 and 72 years respectively, both P < 0.001) (Figure 2).

Conclusion

Influenza A(H1N1)pdm09 is associated with many more severe laboratory-confirmed cases; this is likely due to a more typical clinical presentation and younger patient age, leading to more laboratory testing. In contrast A(H3N2) affects older people and presents more atypically, which is less likely to lead to laboratory testing and confirmation. Focusing on laboratory-confirmed cases, although useful in itself, may provide severely biased estimates of the burden of influenza mortality and morbidity.

Disclosures

All authors: No reported disclosures.
1635. Analysis of Antibiotic-Related Malpractice Claims, 2007 to 2016
Authors: Kabbani Sarah , Greenberg Penny , Falcone Bianca , DeRoo Courtney , Yu-Moe C Winnie , Srinivasan Arjun , Hicks Lauri
Published: October 2019

Background

The threat of medical liability can influence physician behavior and lead to the practice of “defensive medicine.” Concern for malpractice liability has been cited as a cause of inappropriate antibiotic prescribing. Data on malpractice claims related to antibiotic use (AU) are lacking. The objectives of this analysis were to describe malpractice claims associated with AU.

Methods

We conducted a retrospective analysis of pooled closed antibiotic-related claims from a malpractice carrier representing 30% of US malpractice cases from January, 2007 to December, 2016. We described antibiotic-related, malpractice claims, patient demographics, amount of indemnity paid, clinical severity, settings, responsible services, initial diagnoses, drug classes, and causes of allegation.

Results

From 2007 to 2016, 767 antibiotic-related claims were identified and represented less than 1% of overall claims. A total of $123 million were paid for antibiotic-related claims. Claims classified as medium to high clinical severity constituted 97% of all claims, with 35% having permanent injury and 24% leading to death. Of all patients, 56% were female, 8% were < 20 years of age, and 32% were ≥ 60 years old. Most claims (51%) were associated with outpatient settings, 37% with inpatient, and 11% with emergency department settings. Responsible services with the highest number of claims were medicine (44%), surgery (27%) and the emergency medicine (9%). The most common infection cited as an initial diagnosis was respiratory (10%), followed by urinary (7%) and skin and soft-tissue infections (6%). The most common class cited was β-lactams (19%), followed by fluoroquinolones (14%) and sulfa-drugs (11%). Allegations associated with antibiotic administration and management constituted 62% of all claims, 19% were related to failure or delay in diagnosis or treatment, and 19% were due to other causes.

Conclusion

Claims related to AU were not a common cause of malpractice claims in these data source. Antibiotic administration and management was more commonly associated with malpractice claims than failure or delay in AU. A better understanding of malpractice claims associated with AU can help guide messaging on improving antibiotic prescribing.

Disclosures

All authors: No reported disclosures.
1636. Antibiotic Treatment of Human Plague: A Systematic Literature Review of Worldwide Cases, 1937–2016
Authors: Nelson Christina , Fleck-Derderian Shannon , Cooley Katharine , Becksted Heidi , Meaney-Delman Dana , Mead Paul
Published: October 2019

Background

Yersinia pestis remains endemic in countries throughout Africa, Asia, and the Americas and is a tier 1 bioterrorism agent. Antibiotic treatment with aminoglycosides such as streptomycin or gentamicin is effective when initiated early in the course of illness but can have serious side effects. Alternatives such as fluoroquinolones, tetracyclines, and sulfonamides are potentially safer but currently lack robust human data on their efficacy.

Methods

We searched PubMed Central, Medline, Embase, CINAHL, and other databases for articles in any language with terms related to plague, Yersinia pestis, and antibiotics. Articles that contained case-level information on antibiotic treatment and patient outcome were included. We abstracted information related to patient demographics, clinical features of plague, treatment, and survival using a standardized form.

Results

Among 4,874 articles identified and screened, we found 723 published cases of treated plague reported between 1937 and 2016. Fifty-two percent of patients were male; median age was 22 years (range: 8 days-80 years). Cases were most commonly reported from the United States (21%), India (13%), China (11%), Vietnam (10%), and Madagascar (10%). Overall, the case fatality rate was 21%. The majority of patients had primary bubonic (64%), pneumonic (21%), or septicemic (4%) plague, of which survival was 83%, 71%, and 55%, respectively. Among those treated with an aminoglycoside (n = 386, 53%), survival was 86%. Among those treated with a tetracycline (n = 145, 20%), fluoroquinolone (n = 45, 6%), or sulfonamide (n = 311, 43%), survival was 90%, 84%, and 77%, respectively. Survival rates did not substantially differ between patients treated with one vs. two classes of antibiotics (table).

Conclusion

Published cases of treated plague offer an opportunity to evaluate the treatment efficacy of different antibiotic classes. In addition to aminoglycosides, tetracyclines, fluoroquinolones, and sulfonamides appear to be effective for plague treatment, although publication bias and low numbers in certain treatment groups may limit interpretation.

Disclosures

All authors: No reported disclosures.
1645. High Seroprevalence and Seroconversion Rate of Borrelia burgdorferi Infection Among Hispanic/Latino Immigrant Workers in Eastern Suffolk County, New York: A Longitudinal-Based Study
Authors: Vilcarromero Stalin , Nunez Ana M , Vivas Katherine , Russo Julianna , Mahmood Saadia , Wellins Anna-Marie , Lopez-Carrillo Ximena , Xu Yun , Yang Xiaohua , Marcos Luis , Arcan Chrisa , Luft Benjamin J
Published: October 2019

Background

Lyme disease, caused by Borrelia burgdorferi, continues to be the most commonly reported vector-borne disease in the United States (US) affecting the public health and the economy. Suffolk County, New York (NY) has one of the highest incidences in NY State affecting primarily the Hispanic/Latino population working in gardening, landscaping, and agriculture (field workers). However, there is a paucity of research among this population. Thus, the aim of this longitudinal study was to assess the current seroprevalence and seroconversion of the Borrelia burgdorferi infection and its risk factors such as sociodemographic, symptoms, tick encounter, and use of the Fatigue Severity Scale, associated with seropositivity in the Hispanic/Latino immigrant worker population of Eastern Suffolk County.

Methods

Recruitment of participants was based on several towns of this County. Following signed informed consent, participants completed a questionnaire and had their blood drawn. Samples were tested using the conventional 2-tiered serological testing for Borreliosis.

Results

Between June 2016 and October 2018, 660 (83.5%) completed Visit 1; 58.8% of them completed elementary school or less, and 56.7% reported earning = or <$20,000 annually, 344 were field workers, from which, 82.3% and 55.2% were male and from Guatemala, respectively. The overall seroprevalence was 7.2% (48/660) but was significantly higher among gardener/Landscapers (11.5%) having an adjusted odds ratio (OR) = 2.02 with a CI = 1.02–4.03. Another significant risk factor was experiencing fevers after a tick-bite (Adjusted OR: 2.08, CI:1.42–5.63). 2.7% (8/292) seroconverted and were gardener/landscaper.

Conclusion

Several barriers to healthcare access, health literacy, and prevention were identified. Gardening/landscaping has an occupational risk in this population. Efforts to educate about tick-borne infections and preventive methods such as vaccinations are warranted for this population.

Disclosures

All authors: No reported disclosures.
1647. Investigating Parents’ Vaccine Hesitancy in the United Arab Emirates: A Cross-Sectional Survey
Authors: Alsuwaidi Ahmed R , Elbarazi Iffat , Al-Hamad Sania , Alali Asma , Aldhaheri Ruwaya , Sheek-Hussein Mohamud
Published: October 2019

Background

Vaccine hesitancy has been declared by the World Health Organization as a top threat to public health in 2019. It has been studied extensively in the Western world but not so among Arabs. The Parent Attitudes about Childhood Vaccines (PACV) survey is a validated instrument for identifying vaccine-hesitant parents; however, Arabic version is not available. This study aimed to assess the reliability of the PACV survey in Arabic language and to determine the prevalence of vaccine hesitancy among parents in the United Arab Emirates (UAE).

Methods

Forward and backward translation of the PACV in Arabic language was carried out. The reliability of the Arabic-PACV survey was tested among parents with children. The same survey was used to study vaccine hesitancy among parents attending seven primary healthcare centers in Al-Ain city, UAE. Univariate analyses were performed to determine the associations between vaccine hesitancy and socio-demographic characteristics.

Results

The Cronbach’s alpha (a measure of internal consistency reliability) for total Arabic-PACV scores was 0.79. Two hundred and sixty-two participants answered the PACV survey (response rate, 74.9%). The majority were mothers (75.9%) in the age group (18–39 years) and more than half (56.3%) had attended university or higher education. Only 29 parents (11.11%, 95% CI = 7.85–15.5) were found to be vaccine-hesitant (score ≥ 50). Socio-demographic characteristics such as education level, number of children and household income did not have any significant association with vaccine hesitancy. However, when using the question “Have you ever decided not to have your child get a shot for reasons other than illness or allergy?” as a surrogate item for vaccine hesitancy, the variable education was significantly associated to this question. More specifically, participants with lower education (n = 110) were more likely to be vaccine-hesitant compared with those with higher education (n = 147), (OR = 4.50, P = 0.026, 95% CI = 1.3–20.7).

Conclusion

The Arabic-PACV survey could serve as a tool in the evaluation of vaccine hesitancy among parents in UAE and other Arabic-speaking countries. The prevalence of vaccine hesitancy among parents in our community is comparable with other populations.

Disclosures

All authors: No reported disclosures.
1663. Community Engagement for Ebola Prevention in Eastern Democratic Republic of Congo
Authors: Mian Qaasim , Masumbuko Claude Kasereka , Hawkes Michael
Published: October 2019

Background

The second largest outbreak of Ebolavirus in history is currently ongoing in Eastern DRC. The epidemic is characterized by social resistance to foreign-led response teams. Trusted local health practitioners, including medical students, may be valuable social mobilizers in this challenging context.

Methods

We report on a student-led educational campaign to increase community awareness and engagement in EVD control efforts. We evaluated student and community participant satisfaction using standardized questionnaires.

Results

The outreach was conducted in November 2018, involving parades, speeches, branded banners and T-shirts, and interpersonal interactions in public spaces. Key messages, linked to previously identified resistant attitudes, included: “Ebola exists in Butembo,” “Bring infected family members to the Ebola Treatment Unit,” and “Leave burials to the official team.” Medical students (n = 355) and community participants (n = 319) evaluated the outreach campaign. Satisfaction was high: 320 (90%) students agreed that medical students could contribute to the EVD response effort, and 233 (73%) community members agreed that the students had helped them understand Ebola in the area. Lower satisfaction scores were associated with self-reported “resistant” attitudes (e.g., intention to hide infected family member from authorities, ρ = -0.25, P < 0.0001), denial of the existence of Ebola in the area (ρ = -0.17, P = 0.0018), and mistrust of the foreign response team (e.g., belief in mercenary motive, ρ = -0.11, P = 0.042). Higher satisfaction scores were associated with the view that local engagement was critical to ending the epidemic (ρ = +0.13, P = 0.017). Both students (77%) and community members (71%) agreed that they were more motivated to combat Ebola as a result of the outreach, suggesting that the activities fostered empowerment.

Conclusion

Medical students can lead satisfactory community engagement and educational activities during an EVD epidemic. As trusted local health agents, medical students may be valuable allies in building public trust and cooperation in this epidemic complicated by social resistance.

Disclosures

All authors: No reported disclosures.