bluuebunny/crossref_metadata_2025_split huggingface dataset:
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

Abstract

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

Abstract

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

Abstract

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

Abstract

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

Abstract

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

Abstract

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

Abstract

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

Abstract

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

Abstract

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.