bluuebunny/crossref_metadata_2025 huggingface dataset:
567. Does Universal Nasal Decolonization with an Alcohol-Based Nasal Antiseptic Reduce Infection Risk and Cost?
Authors: Arden Scott
Published: October 2019

Background

Nasal decolonization with mupirocin to reduce infection risk, has been associated with mupirocin-resistant Staphylococcus aureus (SA). A community hospital identified two patients colonized with methicillin and mupirocin-resistant SA (MRSA), one scheduled for surgery, one for inpatient IV antibiotic therapy. Instead of mupirocin, an alcohol based nasal antiseptic was applied to these patients twice daily for 5 days, resulting in a negative MRSA nasal screening test in both patients. Neither patient developed an infection during or after treatment. Building on this success, a plan was made to assess the impact of universal nasal decolonization to replace screening and contact precautions for MRSA colonized patients, and to reduce surgical site infections (SSI).

Methods

A 12-month project using a before and after design, was initiated in April 2018. The project involved twice daily application of alcohol-based nasal antiseptic for all inpatients, and preoperatively for all surgical patients in addition to existing preoperative chlorhexidine bathing. No other practice change was made during this period. Assessment of impact was planned by comparing the incidence of MRSA bacteremia and SSI at baseline (2017) and after project implementation, in addition to costs avoided with reduction of nasal screening and CP.

Results

Compared with baseline, between April 2018 and March 2019, there was a decrease in MRSA bacteremia from 3/1,000 patient-days to 0/1,000 patient-days, a reduction in CP from 3.78 to 1.53/1,000 patient-days, a reduction in nasal screens from 3,874 to 605, and a reduction of all-cause (Gram-negative and Gram-positive) SSI after all surgical procedures from 3/4,313 procedures to 0/4,872 procedures. After accounting for the cost of the nasal antiseptic, the reduction in gowns, gloves and nasal screening tests resulted in $104,099.91costs avoided.

Conclusion

House-wide application of alcohol-based nasal antiseptic in place of screening and contact precautions, resulted in a reduced incidence of both MRSA bacteremia and SSI for all types of surgical procedures, in addition to significant costs avoided.

Disclosures

All authors: No reported disclosures.
590. Reduction of Endotracheal Colonization by Gram-Negative Bacilli in a Neonatal Intensive Care Unit Through Use of a Novel Drain Cover
Authors: Buck Melissa , Antunes Michael , Kingham Brewster , Polson Shawn W , Eppes Stephen C
Published: October 2019

Background

Splash and aerosolization from sink drains are a source of contamination, particularly by Gram-negative bacilli (GNB), in healthcare facilities. Neonatal Intensive Care Unit (NICU) outbreaks of infection due to GNB have been attributed to NICU sinks. Recent studies found that a dome-shaped drain cover placed in sinks in an adult ICU prevented dispersal of sink drain bacteria to the environment and hands of healthcare providers. Our NICU routinely performs weekly surveillance cultures of all endotracheal tubes (ETT) and has previously reported a correlation of ETT colonizing organisms with bacteria isolated from blood in late onset sepsis. Our objective was to determine whether the use of a drain cover in every sink in a level III 72 bed NICU could lead to a decrease in the isolation of GNB in the ETTs of hospitalized infants.

Methods

All 34 sink drains and basins in an open layout NICU were cultured. Drain covers were then installed and replaced on a routine basis. Weekly endotracheal tube cultures were performed for all intubated infants.

Results

Prior to implementation of drain covers, the most common GNBs cultured from ETTs were, in order, E. cloacae, Klebsiella spp., Acinetobacter spp., and S. maltophilia. The most common organisms isolated from sinks were, in order, P. aeruginosa, Acinetobacter spp. and S. maltophilia. An unusual species, Acinetobacter ursingii, was common in both sinks and endotracheal tubes. Before and after the implementation of drain covers, the median time to first isolation of a GNB was 14 and 17 days, respectively. Prior to draining cover implementation, there were 31 new GNB isolates during 700 ventilator days (rate of 44.3/1000 ventilator days) among infants with any positive ETT cultures. Post drain cover there were 26 new GNB isolates during 900 ventilator days (rate of 28.9/1000 ventilator days). There was a shift in microbial species isolated from ETTs with Klebsiella spp. and S. marcescens predominating after implementation of drain covers.

Conclusion

The use of a novel drain cover in the sinks in a NICU can reduce the frequency of GNB colonizing the ETTs of patients and can lengthen the time to first positivity. Mitigating sinks as a reservoir for GNB may reduce the likelihood of these bacteria infecting a vulnerable population.

Disclosures

All authors: No reported disclosures.
596. Distinct, Segregated Daptomycin-Susceptible and Daptomycin-Nonsusceptible Staphylococcus aureus Populations Associated with Tricuspid-Valve Infective Endocarditis
Authors: Miller Christopher R , Dey Somrita , Smolenski Paula , Kulkarni Pushkar S , Sakoulas George , Monk Jonathan M , Szubin Richard , David. Berti Andrew
Published: October 2019

Background

Loss of daptomycin susceptibility in Staphylococcus aureus is often associated with sequestered foci of infection, driven by selection pressure from both administered antibiotics and host defense peptides. Susceptibility testing of the organism cultured from blood is assumed to parallel that of the infectious foci, such as heart valves. We studied a case of tricuspid valve endocarditis where one leaflet yielded exclusively daptomycin-nonsusceptible S. aureus and another leaflet yielded purely daptomycin-susceptible S. aureus. We examined the responses of the two populations to different anti-staphylococcal therapies to identify regimens effective against both isolates.

Methods

Both isolates were whole-genome-sequenced using Illumina technologies. The presence of heterogeneous daptomycin-resistant subpopulations was assessed by dilution plating and population analysis profiling. One compartment pharmacokinetic/pharmacodynamic modeling was used to simulate different potential antistaphylococcal pharmacotherapies against each isolate. Hemolysin activity was evaluated as a surrogate for accessory gene regulator function.

Results

The daptomycin-susceptible isolate did not demonstrate heteroresistance while the daptomycin-resistant population was uniformly daptomycin nonsusceptible. The daptomycin non-susceptible isolate demonstrated regrowth by 72 hours of simulated treatment with vancomycin (2 g Q12H) or daptomycin (10 mg/kg daily). Adding cefazolin (2 g Q8H) to vancomycin or daptomycin prevented regrowth at 72 hours. The daptomycin-resistant isolate was deficient in hemolysin production suggesting agr dysfunction. Comparative sequencing identified daptomycin-resistant isolate mutations in mprF, purR and agrA.

Conclusion

This case underscores the complex dynamics of the emergence of S. aureus resistance to daptomycin in vivo. Our pharmacokinetic modeling supports combination therapy in the treatment of endovascular MRSA infection. Reduced hemolytic activity supports the hypothesis that agr modulation is associated with persistent infection and/or treatment failure. Ongoing studies will identify features of distinct bacterial populations that promote ecological succession during infection at a sequestered anatomical site.

Disclosures

All authors: No reported disclosures.
608. Emerging Methicillin Resistance Mechanism in mec Gene-Negative Staphylococci not Detected by Reference Methods
Authors: Durand Geraldine , Dupieux-Chabert Celine , Gustave Claude-Alexandre , Bes Michèle , Fruiquière Berangere , Fulchiron Corine , Munoz Lorette , Rivat Sarah , Ranc Anne-gaelle , Vandenesch Francois , Laurent Frederic , Tristan Anne , Martins-Simoes Patricia
Published: October 2019

Background

B-lactam resistance in Staphylococci is mediated by mec genes usually diagnosed by disc diffusion Cefoxitin test (DDFOX) and PCR testing. Here, we report methicillin-resistant Staphylococcus lugdunensis and Staphylococcus aureus strains lacking mec gene misdiagnosed by reference methods. Since the strains are not B-lactamase hyperproducers we investigated the molecular basis of the methicillin resistance.

Methods

We tested 2 S. lugdunensis isolates (SL1, SL2) collected from distinct blood cultures of the same patient and 2 S. aureus isolates (SA1, SA2): (i) by DDFOX, (ii) for Oxacillin MIC by agar dilution (AD), (iii) by VITEK®2 (bioMérieux) for Oxacillin MIC (V2 OXA) and Cefoxitin Screen Test (V2 OXSF), (iv) for mecA, B, C genes by PCR and (v) by whole-genome sequencing (WGS).

Results

The 4 isolates were methicillin susceptible by DD FOX and mec negative. However, all the isolates displayed variable results for V2 OXA MIC (0.5 to ≥4 mg/L) and for V2 OXSF (POSITIVE, NEGATIVE). For SL1 and SL2 isolates, the V2 OXSF growth curve atypical pattern has led to investigating the OXSF wells. The plates inoculated with the broth extracted from the OXSF well showed 2 colony morphotypes (small “P” and regular “G”) for both isolates. The small colonies (SL1P, SL2P) were Oxacillin resistant (V2 OXA MIC≥4; AD MIC = 4) and V2 OXSF POSITIVE whereas the regular colonies (SL1G, SL2G) were Oxacillin susceptible (V2 OXA MIC = 2; AD MIC = 0.5) and V2 OXSF NEGATIVE. The 4 morphotypes were cefoxitin susceptible by DDFOX and mec negative. Interestingly, WGS revealed a GdpP truncation in the N-terminal domain only found in S. lugdunensis small colonies (SL1P, SL2P) phenotypically resistant to Oxacillin. GdpP is a cyclic diadenosine monophosphate phosphodiesterase enzyme which function is the hydrolysis of a signaling nucleotide.

Conclusion

We described mec negative S. lugdunensis and S. aureus strains expressing heterogeneous methicillin resistance detected by the VITEK2 OXSF test. S. lugdunensis subpopulation of small colonies resistant to oxacillin is associated with a truncation of GdpP protein previously described in S. aureus. Interestingly GdpP loss of function in Staphylococci is associated with a reduced growth and may arise as a result of the selective pressure of exposure to B Lactams.

Disclosures

All authors: No reported disclosures.
611. Fosfomycin Resistance of Multidrug-Resistant Escherichia coli and Mechanisms of Fosfomycin Resistance
Authors: Seok Hyeri , Hoon Jeon Ji , Kyoung Choi Hee , Suk Choi Won , Won Park Dae , Mi Wi Yu , Soo Ko Kwan , Ran Peck Kyong
Published: October 2019

Background

Fosfomycin is one of the antibiotics that may be a candidate for the next-generation antimicrobial agents againt multidrug-resistant bacteria. To date, it is known that the resistance rate is not high for Escherichia coli. However, it is necessary to update the fosfomycin resistance rates in E. coli according to the studies that extended spectrum β-lactamase (ESBL) producing E. coli strains are highly resistance to fosfomycin. We evaluated the resistance rate of fosfomycin, the resistant mechanism of fosfomycin in E. coli, and the activity of fosfomycin against susceptible and resistant strains of E. coli.

Methods

A total of 283 clinical isolates was collected from patients with Escherichia coli species during the period of January 2018 to June 2018, in three tertiary hospitals of Republic of Korea. In vitro antimicrobial susceptibility tests were performed in all E. coli isolates using the broth microdilution method according to the Clinical and Laboratory Standard Institute (CLSI). Multilocus sequence typing (MLST) of the Oxford scheme was conducted to determine the genotypes of E. coli isolated. Fosfomycin genes were investigated for all fosfomycin-resistant E. coli strains.

Results

The overall resistance rate to fosfomycin was 10.2%, compared with 53.4%, 46.3%, 41.3%, 31.1%, 10.6%, 2.5%, and 2.1% for ciprofloxacin, cefixime, cefepime, piperacillin/tazobactam, colistin, ertapenem, and amikacin, respectively. The 29 fosfomycin-resistant isolates did not show a clonal pattern on the phylogenetic tree. MurA and glp genes were identified in all strains. FosA3 were identified in two strains and uhp gene were identified in 4 strains. In time-kill curve studies, fosfomycin was more bactericidal than cefixime against all sensitive E. coli strain. Morever, fosfomycin was more bactericidal than piperacillin/tazobactam against ESBL-producing E. coli strain.

Conclusion

The resistant rate of fosfomycin to E. coli is still low. Fosfomycin was active against E. coli including ESBL producing strains.

Disclosures

All authors: No reported disclosures.
635. Genomic Evolution and Progression of Antimicrobial Resistance in a Series of Extensively Drug-Resistant Pseudomonas aeruginosa (XDR-Pa) Isolates from a Cystic Fibrosis Lung Transplant Recipient
Authors: Yasmin Mohamad , Adams Mark D , Marshall Steven , Abbo Lilian , Benjamino Jacquelynn , Krishnan Nikhil , Rojas Laura J , Scott Jacob , Jacobs Michael , Rhoads Daniel D , Perez-Cardona Armando , Martinez Octavio , Perez Federico , Bonomo Robert A
Published: October 2019

Background

Chronic respiratory infection due to extensively drug-resistant Pseudomonas aeruginosa (XDR-Pa) is a significant cause of mortality in cystic fibrosis (CF) patients. The CF respiratory anatomy, chronic antibiotic use, and PA colonization creates a milieu for high evolutionary pressure and genetic diversity. We sought to explore the progression of antibiotic resistance and genome evolution of XDR-Pa in a longitudinal series of isolates collected from an18-year-old CF patient who underwent lung transplantation.

Methods

Consecutive respiratory isolates were collected from December 2016 to March 2018. Standard disk diffusion methods were used to evaluate antimicrobial susceptibility. Whole-genome sequencing (WGS) data were obtained on an Illumina NextSeq and assembled. Variants were identified using the GATK HaplotypeCaller and their functional impact was determined using snpEff. Maximum likelihood phylogenetic trees were constructed using MEGA and BEAST. Panther was used to test for enrichment of Gene Ontology functional categories among mutated genes.

Results

Phylogenetic analysis of complete genome sequences showed that 18 isolates formed a monophyletic group. Analysis using BEAST showed that genomes shared a common ancestor that was present prior to transplant. Over 300 single nucleotide variants and small insertion-deletion mutations were found, in comparison with a reconstruction of the ancestral sequence (Figure 1). Shared patterns of antibiotic susceptibility profiles were largely concordant with phylogenetic clustering and trended toward a decrease in susceptibility over time. Two different frameshift mutations in the DNA mismatch repair gene mutL were found in 15 genomes and these exhibited an increased rate of transition to transversion mutations, consistent with a hypermutator phenotype.

Conclusion

WGS of XDR-Pa identified variations in antibiotic resistance and virulence genes. Changes in mutL likely accelerated the accumulation of mutations. Multiple related sub-groups of strains appear to have been circulating prior to transplant and continued to diverge during the treatment period. Correlating antibiotic pressure, susceptibility profiles, and WGS in XDR-Pa from a single patient reveals the clinical impact of genomic evolution in CF.

Disclosures

All authors: No reported disclosures.
638. Comparative Genomics of Mycoplasma pneumoniae Isolated From Children with Pneumonia: South Korea, 2010–2016
Authors: Lee Hoan J , Kee Lee Joon , Young Choi Yun , Young Park Ji , Seong Moon-Woo , Hwa Choi Eun
Published: October 2019

Background

This study applied high-throughput whole-genome sequencing (WGS) technologies to investigate the comparative genomics of 30 M. pneumoniae strains isolated from children with pneumonia in South Korea during two epidemics from 2010 to 2016 in comparison with a global collection of 48 Mycoplasma pneumoniae strains which includes seven countries ranging from 1944 to 2017.

Methods

A total number of 30 M. pneumoniae strains were selected for whole-genome sequence analysis from two epidemics, 2010–2012 and 2014–2016. Next-generation sequencing (NGS) of all M. pneumoniae strains was performed using the Illumina MiSeq desktop sequencer. Comparative genomic analysis was performed using BLAST Ring Image Generator (BRIG), MAUVE, MAFFT, CLC Phylogeny Module, SnpEff, and Pathosystems Resource Integration Center (PATRIC).

Results

The 30 Korean strains had approximately 40% GC content and ranged from 815,686 to 818,669 base pairs, coding for a total of 809 to 828 genes. Overall, BRIG revealed 99% to>99% similarity among strains. The genomic similarity dropped to approximately 95% in the P1 type 2 strains when aligned to the reference M129 genome, which corresponded to the region of the p1 gene. MAUVE detected four subtype-specific of which were all hypothetical proteins except for one tRNA insertion in all P1 type 1 strains. eBURST analysis demonstrated two clonal complexes which are accordant with the known P1 typing, with higher diversity among P1 type 2 strains. The phylogenetic tree constructed with 78 genomes including 48 genomes outside Korea, formed three clusters, in which the sequence type 3 strains from Korea were divided into two P1 type 1 clusters.

Conclusion

The comparative genomics of the 78 M. pneumoniae strains including 30 strains from Korea by WGS reveals structural diversity and phylogenetic associations, even though the similarity across the strains was very high.

Disclosures

All authors: No reported disclosures.
642. Higher Diagnostic Accuracy with Ultrasensitive Detection of Helicobacter pylori Stool Antigen Using Single-Molecule Counting Technology
Authors: Katzenbach Phoebe , Dave Gipshu , Mukherjee Ali , Sandlund Johanna , Estis Joel , Nolan Niamh , Banaei Niaz , Noland Brian
Published: October 2019

Background

Current diagnostic methods for Helicobacter pylori infection include fecal antigen tests, 13C-urea breath test, and gastric biopsy. The breath test is limited by poor specificity and the fecal antigen tests by poor sensitivity. We have developed a prototype assay for detection of H. pylori antigen in human stool, powered by ultrasensitive Single Molecule Counting technology, and compared the analytical performance to a commercially available enzyme-linked immunoassay (EIA) antigen test.

Methods

The Singulex Clarity H. pylori antigen assay incubates diluted stool with capture and fluorescent-labeled detection antibodies. After incubation and wash steps, fluorescent molecules are eluted and single-molecule fluorescence measured by detected events (DE′). Analytical performance was compared with a commercial EIA (Premier Platinum HpSA® Plus, Meridian Bioscience, Inc.) using serial dilutions of H. pylori control (~37,500–1.7 ng/mL) and high positive stool (signal to noise ratio >2). Clinical performance was evaluated using two cohorts, one had 10 EIA-negative and 10 EIA-positive samples and the other 13 high positives (> 0.500 at 450/630) and 5 low positives near the EIA cutoff (0.100–0.500 at 450/630). One sample was excluded due to discordant EIA results, and three to reader flags.

Results

The lower limit of detection of the Clarity H. pylori assay was 1.7 ng/mL and the EIA 1,250 ng/mL (IFU: LOD 4.67 ng/mL). A high positive stool sample was detectable by the Clarity H. pylori assay diluted 1:10,000,000 and by the EIA 1:10,000. The Clarity H. pylori assay showed a 729-fold increase in lower limit of detection and 1,000-fold increase in endogenous antigen lower limit of detection compared with the EIA. Clarity signal ranged from 46–665 DE’ for EIA-negative samples and 487,484–576,747 DE’ for EIA-positive samples.

Conclusion

The Singulex Clarity H. pylori antigen assay may have orders of magnitude higher analytical sensitivity than the commercial EIA and demonstrated 100% positive agreement and 100% negative agreement on detection of H. pylori antigen in human stool samples. The ultrasensitive Clarity H. pylori assay has the potential for high sensitivity and specificity to improve current diagnostic options for H. pylori infection; however, additional multicenter studies are required.

Disclosures

All authors: No reported disclosures.
645. Singulex Clarity Norovirus Assay (In Development) Provides Ultrasensitive Detection of Norovirus Genogroups I and II
Authors: Dave Gipshu , Katzenbach Phoebe , Sandlund Johanna , Estis Joel , Mukherjee Ali , Nolan Niamh , Almazan Anna , Hadass Orr , Noland Brian , Bishop Jeffrey J , Banaei Niaz , Riner Diana K , Todd John
Published: October 2019

Background

Commercially available enzyme immunoassays (EIAs) for detection of norovirus antigen have poor sensitivity and are limited to use in investigations of a gastroenteritis outbreak. Hence, there remains a need for a standalone high-sensitivity assay that enables rapid and accurate detection of norovirus antigen.

Methods

The Singulex Clarity norovirus assay is currently in development for use on the Singulex Clarity® system (Singulex Inc., Alameda, CA, USA), a fully-automated platform powered by Single Molecule Counting technology (registered with the FDA and CE marked). The assay uses paramagnetic microparticles bound to capture antibody and a fluorescently labeled reporter antibody to detect virion capsid protein of norovirus genogroups I (GI) and II (GII) in the stool. For the development of Clarity Norovirus assay, diagnostic performance of 4 antibody pairs (as Capture and Detection reagent) were evaluated by testing 137 stool samples from patients with suspected norovirus infection. Samples were sourced from three providers: (1) 90 genotyped samples of which 75 were positive (19 different genotypes) and 15 were negative by the CDC assay, (2) 3 samples positive and 5 samples negative by the BioFire® FilmArray® Gastrointestinal Panel, and (3) 39 samples negative by a lab-developed test using Cepheid reagents (SmartCycler®).

Results

From all the antibody pairs tested, one of the pairs had best performance with the area under the receiver operating characteristic (AuROC) curve demonstrating a C-Statistic of 0.959 (95% CI 0.921–0.997), compared with AuROC C-statistic of 0.943 (95% CI 0.896–0.990), 0.871 (95% CI 0.807–0.936), and 0.914 (95% CI 0.863–0.964) for the three other pairs. The Clarity assay detected all 19 different genotypes tested (figures).

Conclusion

The ultrasensitive and rapid Clarity norovirus assay (in development) for detection of GI and GII demonstrated excellent performance with one of the antibody pairs tested and detected all 19 tested genotypes. The Clarity assay may offer a standalone solution for norovirus diagnostics.

Disclosures

All authors: No reported disclosures.
651. Multi-Center Evaluation of the BioFire® FilmArray® Blood Culture Identification 2 Panel for the Detection of Microorganisms and Resistance Markers in Positive Blood Cultures
Authors: Lu Yang , Hatch Joseph , Holmberg Kristen , Hurlock Anna , Drobysheva Daria , Spaulding Usha , Vourli Sophia , Pournaras Spyridon , Everhart Kathy , Leber Amy , Barr Becki , Daly Judy , Henry Tai , Johnson Amy , Balada-Llasat Joan-Miquel , Rhoads Daniel D , Jacobs Michael , Mc Kinley Kathleen , Harrington Amanda , Zhang Frank , Berry Gregory J , Hyung Jeong Moon , She Rosemary , Sambri Vittorio , Fantini Michela , Dirani Giorgio , Zannoli Silvia , Bourzac Kevin
Published: October 2019

Background

The BioFire® FilmArray® Blood Culture Identification 2 (BCID2) Panel is a diagnostic test that provides results for 26 bacterial, 7 fungal pathogens and 10 antimicrobial resistance (AMR) genes from positive blood culture (PBC) specimens in about an hour. The BCID2 Panel builds upon the existing BCID Panel with several additional assays that include Candida auris and an expanded AMR gene menu that provides methicillin-resistant Staphylococcus aureus (MRSA) results plus detection for mcr-1, carbapenem resistance, and ESBL. Here, we summarize studies conducted to establish clinical performance using an Investigational Use Only version of the BCID2 Panel.

Methods

Three studies were performed. The first involves prospective collection and testing of an expected ~1,000 residual PBCs at 7 US and 2 EU sites, which began in October 2018 and will conclude in June 2019. BCID2 Panel performance is compared with reference methods of microbial culture as well as PCR/sequencing for AMR genes. In addition, BCID2 Panel MRSA results are compared with the FDA-cleared Xpert MRSA/SA BC system (Cepheid, Inc). Relevant bacterial isolates recovered from PBCs are also evaluated by various phenotypic antimicrobial susceptibility testing (AST) methods. The prospective evaluation is supplemented with a second study that involves testing of ~300 pre-selected, archived PBCs containing rare organisms. The third study includes over 500 seeded blood cultures containing very rare organisms with an evaluation of co-spiked samples.

Results

With over 1,200 samples tested to date (out of an anticipated 1,800 total), the BCID2 Panel has demonstrated an overall sensitivity of >98% and specificity of >99% for identification of microorganisms compared with culture. Concordance between the BCID2 Panel and the Xpert MRSA/SA BC test is >99% for identification of MRSA. Evaluation of BCID2 Panel AMR gene detection relative to AST and PCR is ongoing.

Conclusion

The FilmArray® BCID2 Panel appears to be a sensitive, specific, and robust test for rapid detection of microorganisms and MRSA in PBCs. With the use of this comprehensive test, improved antimicrobial stewardship is anticipated.

Disclosures

All authors: No reported disclosures
664. Efficacy in Adults With Moderate to Severe Community-Acquired Bacterial Pneumonia (CABP) and Pneumonia Outcomes Research Team (PORT) Risk Class III to V: Results of a Pooled Analysis of Lefamulin Evaluation Against Pneumonia (LEAP) 1 and LEAP 2 Study Outcomes
Authors: Alexander Elizabeth , Schranz Jennifer , Das Anita F , Moran Gregory J , Sandrock Christian , File Thomas M , Gelone Steven P
Published: October 2019

Background

CABP, the second most common cause of hospitalization in the US, has prognoses ranging from rapid resolution to death, the likelihood of which can be estimated via PORT pneumonia severity index. Patients with PORT scores ≤III have predicted mortality rates <3% and may be managed as outpatients; those with scores of IV/V are often hospitalized, owing to higher predicted mortality rates (8%–31%). Lefamulin (LEF), a novel systemic antibiotic, was noninferior to moxifloxacin (MOX) for treatment of adults with CABP in 2 phase 3 trials (LEAP 1 and 2). We report the results of pooled analyses of LEAP 1/2 data in patients with PORT III and IV/V scores.

Methods

In LEAP 1, patients (PORT III–V) received IV LEF 150 mg for 5–7 d or MOX 400 mg for 7 d, with optional IV-to-oral switch. In LEAP 2, patients (PORT II–IV) received oral LEF 600 mg for 5 d or MOX 400 mg for 7 d. In both studies, randomization was stratified by PORT score. The studies assessed early clinical response (ECR; 96±24 h after first dose) in the intent-to-treat (ITT; all randomized patients) population (FDA primary endpoint) and investigator assessment of clinical response (IACR) success at test of cure (5–10 d after last dose) in the modified ITT (received ≥1 dose) and clinically evaluable (met predefined evaluability criteria) populations (EMA coprimary endpoints).

Results

Over 50% of patients (52.8% LEF; 51.9% MOX) were PORT III and >18% (18.7% LEF; 18.2% MOX) were PORT IV/V, reflective of the CABP population. As expected, PORT IV/V patients were older and more likely to have comorbidities (eg, moderate/severe renal impairment) vs. PORT III patients (Table 1). ECR and IACR response rates were high and similar for LEF and MOX in PORT III (Figure 1) and PORT IV/V (Figure 2) patients, with slightly higher rates in PORT III vs. PORT IV/V patients. LEF and MOX had similar safety profiles, with more adverse events overall in PORT IV/V vs. PORT III patients (Table 2). Mortality rates were low, with higher rates in PORT IV/V (4.2% LEF; 5.2% MOX) vs. PORT III (1.5% LEF; 0.6% MOX) patients.

Conclusion

ECR and IACR rates with LEF were high and similar to MOX in patients who are candidates for outpatient (PORT III) and inpatient (PORT IV/V) treatment; LEF may be an alternative oral and IV monotherapy option for empiric CABP treatment in both populations.

Disclosures

All authors: No reported disclosures.
692. In Vitro Antibacterial Activity of Cefiderocol Against a Multi-national Collection of Carbapenem-Nonsusceptible Gram-Negative Bacteria From Respiratory Infections: SIDERO-WT-2014–2017
Authors: Rao Sonia N , Nguyen Sean T , Soriano Melinda M , Hayes Jennifer M , Hackel Meredith M , Sahm Daniel F , Tillotson Glenn S , Echols Roger , Tsuji Masakatsu , Yamano Yoshinori
Published: October 2019

Background

Cefiderocol (CFDC) is a new siderophore cephalosporin with potent in vitro activity against a broad range of Gram-negative (GN) pathogens, including carbapenem-nonsusceptible (Carb-NS) strains. We evaluated the in vitro activity of CFDC and comparator agents against recent clinical Carb-NS GN respiratory isolates collected from North America and Europe as part of the multi-national SIDERO-WT surveillance program.

Methods

A total of 2831 Carb-NS GN respiratory isolates collected from 2014 to 2017 were tested centrally (IHMA, Inc., Schaumburg, IL). Minimum inhibitory concentrations (MIC) were determined for CFDC, cefepime (FEP), ceftazidime–avibactam (CZA), ceftolozane-tazobactam (C/T), ciprofloxacin (CIP), colistin (CST), and meropenem (MEM) by broth microdilution and interpreted according to the 2018 CLSI guidelines. CFDC MICs were tested in iron-depleted cation-adjusted Mueller–Hinton broth, and interpreted according to the 2018 CLSI provisional breakpoints. Carb-NS strains were defined as MEM MIC of ≥2 µg/mL for Enterobacteriaceae (ENB) and of ≥4 µg/mL for nonfermenters (NF).

Results

CFDC exhibited predictable in vitro activity against 2807 clinically relevant Carb-NS GN isolates (214 ENB, 1086 A. baumannii complex, 693 P. aeruginosa, 794 S. maltophilia, and 20 Burkholderia cepacia) isolated from respiratory infections. CFDC was the most active agent against Carb-NS ENB with 97.7% susceptibility followed by 78.0% CZA, 59.4% CST, and 16.4% CIP. Against Carb-NS A. baumannii complex, CFDC demonstrated 94% susceptibility vs. 83.7% for CST. CFDC was the most active agent against Carb-NS P. aeruginosa with 99.9% susceptibility followed by 97.8% CST, 77.6% C/T, and 77.5% CZA. 99.7% of S. maltophilia and 100% of B. cepacia isolates had CFDC MICs of ≤4 µg/mL. The MIC90s of tested compounds for clinically relevant pathogens are shown in the table.

Conclusion

In a multinational collection of Carb-NS GN respiratory isolates, CFDC demonstrated potent in vitro activity with MIC90 of ≤4 µg/mL for all clinically relevant ENB and NF. These findings suggest that CFDC can be a potential option for the treatment of respiratory infections caused by Carb-NS ENB, A. baumannii complex, P. aeruginosa, S. maltophilia, and B. cepacia.

Disclosures

All authors: No reported disclosures.
700. Safety and Efficacy of Omadacycline in Patients with Diabetes in Phase 3 Clinical Studies
Authors: Pai Manjunath P , Wilcox Mark H , Curran Marla , Chitra Surya , Garrity-Ryan Lynne , McGovern Paul C
Published: October 2019

Background

The risk of serious infections and poor treatment outcomes is reported to be higher in patients with diabetes compared with the general population. Omadacycline (OMC) is an intravenous (IV) and oral aminomethylcycline antibiotic approved in the US to treat acute bacterial skin and skin structure infections (ABSSSI) and community-acquired bacterial pneumonia (CABP) in adults. Here we assessed safety and efficacy results from OMC Phase 3 studies (ABSSSI: Omadacycline in Acute Skin and skin structure Infections Study [OASIS]-1 and OASIS-2; CABP: Omadacycline for Pneumonia Treatment In the Community study [OPTIC]), by diabetes history.

Methods

In OASIS-1 (IV to optional oral medication) and OASIS-2 (oral only), patients were randomized to OMC or linezolid (LZD) for 7–14 days. In OPTIC, patients were randomized to IV OMC or moxifloxacin (MOX) for 7–14 days, with optional transition to oral medication. Data from OASIS-1 and OASIS-2 were pooled, and patient subgroups were defined by any medical history of diabetes (type 1, type 2, or unspecified), or no medical history of diabetes. Efficacy outcomes were early clinical response (ECR) and investigator’s assessment of clinical response at post-treatment evaluation (PTE), as defined for each indication. Safety was assessed by treatment-emergent adverse events (TEAEs) and laboratory measures, and data were pooled across the three studies.

Results

A total of 2,150 patients were included, of whom 238 (11.1%) had any history of diabetes (n = 105 for ABSSSI, n = 133 for CABP). In the pooled ABSSSI studies and the CABP study, clinical success at ECR and PTE was similar between patients with or without diabetes, and between OMC and the respective comparator (figure). TEAEs and serious TEAEs, respectively, were reported in similar numbers of OMC-, LZD-, and MOX-treated patients with diabetes (41.8–49.3%, 4.5–7.0%) and without (41.2–48.3%, 1.6–6.9%). Rates of nausea and vomiting, respectively, in patients with diabetes were similar across treatment arms: OMC (5.0%, 5.0%), LZD (7.5%, 6.0%), MOX (7.0%, 2.8%).

Conclusion

Omadacycline efficacy and safety were similar and consistent in patients with or without diabetes.

Disclosures

All authors: No reported disclosures.
709. In Vitro Antibacterial Activity and In Vivo Efficacy of Sulbactam–Durlobactam (ETX2514SUL) Against Pathogenic Burkholderia Species
Authors: O’Donnell John , Miller Alita , Lane Douglas , Panchal Rekha , Mueller John P
Published: October 2019

Background

The genus Burkholderia contains several pathogenic species with distinct etiologies, including Burkholderia pseudomallei the biothreat pathogen responsible for melioidosis and Burkholderia mallei which causes glanders. β-Lactams, such as ceftazidime and meropenem, are important therapeutic options for these infections. However, clinical resistance to β-lactams, which is primarily mediated by multiple types of β-lactamases in these species, is a growing concern. Durlobactam (ETX2514, DUR) is a novel β-lactamase inhibitor with broad-spectrum activity against Ambler class A, C, and D β-lactamases. Sulbactam (SUL) is an Ambler Class A β-lactamase inhibitor with intrinsic antibacterial activity against a limited number of species, including Acinetobacter spp. SUL-DUR is currently in Phase 3 clinical testing for the treatment of carbapenem-resistant infections caused by Acinetobacter spp. In this study, SUL-DUR was tested for in vitro antibacterial activity against B. pseudomallei and B. mallei as well as for in vivo efficacy in a preclinical model of melioidosis.

Methods

The antibacterial activity of SUL alone or in combination with DUR (fixed at 4 mg/L) against B. pseudomallei (n = 30) and B. mallei (N = 28) was determined following CLSI guidelines. In vivo efficacy was tested in an acute murine model of melioidosis in which 4 × 104 cfu Bp K96423 (SUL-DUR MIC = 1 mg/L) was administered intranasally to BalbC mice. SUL-DUR (100/200 or 400/200 mg/kg) was administered q4h subcutaneously 4 hours post-challenge for 6 days and murine survival was monitored for 45 days. Doxycycline (DOX) and ciprofloxacin (CIP) were dosed as positive controls at 40 mg/kg q12 h for 6 days.

Results

The addition of DUR effectively lowered the SUL MIC50/90 from 8/16 to 0.25/0.5 mg/L vs. B. pseudomallei and from 8/8 to 1/2 mg/L for B. mallei. All untreated mice in the melioidosis model succumbed to infection within 3 days of challenge. 60% survival was observed for both dose arms of SUL-DUR as compared with 40% survival observed for both CIP and DOX.

Conclusion

Preliminary preclinical data demonstrating robust in vitro and in vivo antibacterial activity of SUL-DUR against Burkholderia spp. suggests this combination may be an effective new therapy for the treatment of these challenging pathogens.

Disclosures

All authors: No reported disclosures.
725. WCK 5222 (Cefepime/Zidebactam): An In Vitro Assessment of Activity Compared with Current Dual-Antibiotic Options Against Multidrug-Resistant Pseudomonas aeruginosa
Authors: Mullane Elias M , Avery Lindsay M , Nicolau David P
Published: October 2019

Background

Pseudomonas aeruginosa (PSA) is an opportunistic pathogen known to cause complications in critically ill patients worldwide. In those at risk of infection with multidrug-resistant strains (MDR-PSA), dual antibiotic therapy is often considered. However, this practice may contribute to rising resistance rates and poor outcomes if empirical selection is suboptimal. WCK 5222 (cefepime/zidebactam), a novel β-lactam/β-lactam enhancer, may offer a solution.

Methods

Minimum inhibitory concentrations (MICs) were determined for WCK 5222, amikacin (AMK), fosfomycin (FOF), cefepime (FEP), ceftolozane/tazobactam (C/T), and meropenem (MEM) against 18 clinical PSA isolates using gradient diffusion strip (GDS) methods. Activities of FEP, C/T, and MEM in combination with AMK and FOF were assessed using GDS for isolates nonsusceptible to the β-lactam (MICs >8 mg/L, >4/4 mg/L, and >2 mg/L, respectively). Synergy was defined as a fractional inhibitory concentration index ≤ 0.5. Instances of restored β-lactam susceptibility when tested in combination were compared with the proportion of WCK 5222 MICs ≤ 8 mg/L.

Results

WCK 5222 MICs ranged from 2 to 32 mg/L (MIC50, 8 mg/L). Rates of susceptibility were: AMK (67%), FOF (44%, MIC ≤ 64 mg/L), FEP (6%), C/T (33%), MEM (0%). Combinations with C/T most frequently demonstrated synergy (C/T-FOF, 42%; C/T-AMK, 33%) and restored C/T susceptibility was observed in 42% of assessments with FOF and in 50% with AMK. For FEP combinations, synergy was observed in 29% and 18% of assessments with FOF and AMK, respectively, with restored susceptibility in 6% for both combinations. Synergy occurred in 11% and 6% of assessments of MEM with FOF and AMK, respectively, with zero instances of restored susceptibility. In total, β-lactam susceptibility was restored in 14% (13/94) of combinations compared with 78% (14/18) of WCK 5222 MICs ≤ 8 mg/L.

Conclusion

In a selection of MDR-PSA isolates that included carbapenem- and C/T-resistant strains, WCK 5222 MICs ≤ 8 mg/L (cefepime susceptible) were observed more frequently than restoration of susceptibility in select β-lactams in combination with FOF or AMK. WCK 5222 monotherapy may offer enhanced coverage of MDR-PSA over empirically selected combination therapies.

Disclosures

All authors: No reported disclosures.
728. Activity of Eravacycline Against Contemporary Gram-Negative Clinical Isolates From New York City Hospitals
Authors: Iregui Alejandro , Khan Zeb , Landman David , Quale John M
Published: October 2019

Background

Antibiotic-resistant Gram-negative bacteria, including KPC-producing Enterobacteriaceae and carbapenem-resistant A. baumannii, have been problematic hospital pathogens in NYC and other areas. Eravacycline (ERV), a fluorocycline antibiotic released in the USA in 2018, has demonstrated in vitro activity against many of these strains. We tested the activity of ERV against a recent collection of clinical isolates from NYC hospitals.

Methods

For a 3-month period in 2017, all unique patient isolates of E. coli, K. pneumoniae, Enterobacter spp., and A. baumannii were collected from 7 hospitals in Brooklyn, NY. MICs were performed by broth microdilution for ERV and Tigecycline (TGC) and agar dilution for other antibiotics according to CLSI methodology. Cephalosporin-resistant isolates were screened by PCR for common carbapenemases.

Results

The susceptibility results for tetracycline and ERV are listed in the Table. Overall, 95% of the Enterobacteriaceae were inhibited by ≤ 0.5 μg/mL of ERV, the FDA-suggested breakpoint. Of 1,876 isolates of E. coli, 4 possessed KPC. ERV MICs for these 4 isolates were 0.125–0.25 μg/mL. Of 518 isolates of K. pneumoniae, 20 possessed KPC. The ERV MIC50 and MIC90 for these isolates were 1 and 1 μg/mL, respectively. Of 172 isolates of Enterobacter spp., 3 possessed KPC. ERV MICs for these 3 isolates were 0.5–1 μg/mL. Of 45 isolates of A. baumannii, 11 isolates possessed a carbapenemase (OXA23 in 8, OXA24 in 2, and KPC in 1). The ERV MIC50 and MIC90 for these isolates were 1 and 2 μg/mL, respectively. Overall, ERV MICs were two-fold lower than TGC MICs for A. baumannii.

Conclusion

ERV possesses significant in vitro activity against contemporary clinical isolates of Enterobacteriaceae and A. baumannii from NYC, including many carbapenemase producing strains.

Disclosures

All authors: No reported disclosures.
731. Pharmacokinetics of Gepotidacin (GSK2140944) in Subjects with Hepatic Impairment
Authors: Hands Jonathan T , Tao Yu , Tiffany Courtney , Perry Caroline R , Dumont Etienne , Hossain Mohammad
Published: October 2019

Background

Gepotidacin (GEP), a first in class novel triazaacenaphthylene bacterial topoisomerase inhibitor, inhibits bacterial replication and has in vitro and in vivo efficacy activity against key pathogens, including drug-resistant strains, associated with a range of infections. In a previous absorption, distribution, metabolism, and excretion study for GEP, the mean recovery of radioactivity in urine and feces accounted for approximately 31.2% and 52.5%, respectively, of [14C]-GEP administered as a single oral dose. GEP was eliminated mainly as parent in urine, accounting for approximately 20% of the administered dose. Elimination via metabolism accounted for a total of 13% to 19% of the dose. Average total intravenous clearance of approximately 43 L/hour and renal clearance (CLr) of approximately 16 L/hour provides a hepatic clearance of 27 L/hour, suggesting that hepatic clearance is a major route of elimination of GEP.

Methods

Participants with normal and varying degrees of hepatic impairment (HI) received a single oral dose of GEP 1,500 mg. PK collections of blood, urine and saliva were performed.

Results

Relative to normal hepatic function, GEP Cmax and AUC(0-∞) in plasma were increased by 1.2-fold in subjects with moderate, and between 1.7-fold to 1.9-fold in severe HI. The fraction of dose excreted in urine increased with an increase in hepatic impairment. GEP urine concentrations remained high over a 12-hour period. Saliva concentrations displayed a linear relationship with plasma (both total and unbound) concentrations (R2 = 0.76). The geometric mean ratio of saliva AUC to unbound plasma AUC values ranged from 0.746 to 0.839 across all groups. Administration of 1,500 mg oral GEP was generally tolerated.

Conclusion

An increase in the dosing interval or dose reduction may be required in patients with severe hepatic impairment.

Disclosures

All authors: No reported disclosures.
737. Novel Glycans Reduce Carbapenem-Resistant Enterobacteriaceae and Vancomycin-Resistant Enterococci Colonization in an Ex Vivo Assay by Supporting Growth and Diversity of Commensal Microbiota at the Expense of MultiDrug-Resistant Organisms (MDRO)
Authors: LeBlanc Gabby , Brooks Brandon , Hartman Madeline , Hecht Maxwell B , Luong Hoa , Pan Zheng , Sofen Stephen , Miller Kelsey J , Meehan Brian , Mahowald Michael A , Yatsunenko Tanya
Published: October 2019

Background

Infections with Carbapenem-resistant Enterobacteriaceae (CRE) and vancomycin-resistant Enterococci (VRE) can result in a 50% mortality rate in compromised hosts. A major risk factor for clinical infection is intestinal colonization with CRE or VRE. There are currently no FDA-approved compounds to decolonize these organisms from the gastrointestinal tract (gut). Commensal microbes offer protection from pathogen infection; however, in immunocompromised hosts or with antibiotic treatment, the protective properties of the microbial community are compromised, leaving the gut susceptible to pathogen colonization. Higher concentrations of pathogens within the gut correlate with an increased risk of infection with MDROs. Our hypothesis is that reducing colonization of the gut with MDROs would reduce the likelihood of a clinical infection.

Methods

Kaleido built a platform that emulates the gut environment and allows for high throughput screening of Kaleido’s Microbiome Metabolic Therapies (MMT™) in human gut microbiomes ex vivo. Over 500 compounds were screened for their ability to reduce the levels of CRE and VRE in fecal microbial communities from both healthy subjects and critically ill patients receiving broad-spectrum antibiotics.

Results

Kaleido’s lead MMTs selectively favor the growth of the commensal microbiota at the expense of pathogens, resulting in a decrease of CRE and VRE from 80% of the initial community to 5% in a single batch culture, as measured by 16S rRNA gene and shotgun metagenomic sequencing. Lead MMTs do not support growth of CRE and VRE strains in culture, nor of other pathogens frequently encountered in critically ill and immunocompromised patients, such as Clostridium difficile and common fungal pathogens.

Conclusion

These results suggest that intervention with MMTs may reduce CRE and VRE colonization and support further evaluation in patients colonized with CRE or VRE pathogens.

Disclosures

All authors: No reported disclosures.
742. The Development, Implementation, and Feasibility of Multidisciplinary Treatment Planning Conference for Individuals with Unstable Substance Use Disorders and Active Infections Requiring Prolonged Antimicrobial Therapy: The OPTIONS-DC Model
Authors: Strnad Luke , Douglass Alyse , Young Kathleen , Mayer Heather , Brown Jessica , Mahoney Stacey , Dellabough-Gormley Elona , Gore Sara J , Englander Honora , Gregg Jessica , Sikka Monica , Sikka Monica
Published: October 2019

Background

Outpatient parenteral antimicrobial therapy (OPAT), widely used for serious infections, has high failure rates in people with substances use disorders (SUD)1–2. At our institution, completing therapy in the hospital was previously the best option for high-risk patients; but long hospital stays are often unacceptable to patients and costly. To improve outcomes, our Infectious Diseases division, OPAT program, and Improving Addiction Care Team (IMPACT) developed and implemented a novel multidisciplinary conference (OPTIONS-DC) for inpatients with SUD requiring prolonged antibiotics. This study describes the conference development, tool, and initial experience.

Methods

From June 2017 to June 2018, diverse stakeholders collaboratively created and implemented a structured conference to discuss treatment options that balance medical efficacy, patient preferences, and feasibility using harm-reduction principles. After 10 months of hospital-wide implementation, we elicited provider feedback and performed a content analysis of OPTIONS-DC notes and patient records to evaluate the impact.

Results

The goal of conference development was prioritizing patient preferences and engaging multidisciplinary input. One RN facilitates the conference using the tool (Figure 1) to elicit input from the relevant providers. The tool systematically addresses components that may predict treatment success (i.e., working phone) while emphasizing patient preference and harm reduction. The IMPACT social work PICC safety assessment informs risks for IV access. Antibiotic recommendations are not a binary of optimal/suboptimal choices for the infection but options that best fit patient context. The average conference length was 28 minutes (IQR 21). Preliminary data shows good clinical outcomes and savings to inpatient days and cost. Initial feedback suggests the model was positively experienced by medical providers (Figure 2) and supported patient preferences.

Conclusion

A multidisciplinary patient-centered conference that prioritizes patient preference and uses harm-reduction principles for this high-risk population is practical, effective, and positively experienced by providers. This model may serve as a roadmap for other institutions.

Disclosures

All authors: No reported disclosures.