bluuebunny/crossref_metadata_2025 huggingface dataset:
547. Multidrug-Resistant Pseudomonas aeruginosa in an Academic Regional Burn Intensive Care Unit
Authors: Estelle Carolee D , Sreeramoju Pranavi , Collinsworth Katherine A , Gaffney Donna , Yerks Lisa , Blast Daniel L , Hollaway Rita , Cavuoti Dominick , Voy-Hatter Karla , Ehrhart Kathryn L , Potithavoranant Katrina , Perl Trish M , Perl Trish M
Published: October 2019

Background

Pseudomonas aeruginosa infection can lead to morbidity, mortality and increased hospital length of stay especially in Burn Intensive Care Units (BICU) patients. Reports of multi-drug-resistant Pseudomonas aeruginosa outbreaks in the BICU are increasing. We investigated the epidemiology of Carbapenem-Resistant Pseudomonas aeruginosa (CRPA) in our BICU.

Methods

Clinical and laboratory characteristics of all CRPA isolates identified between 5/8/16 and 3/14/19, in an 11-bed BICU in an academic 870-bed public safety-net hospital were reviewed and defined as Meropenem MIC 4 or greater. Retained isolates were sent for pulse-field gel electrophoresis (PFGE). Infection prevention (IP) observations and interventions were intensified and environmental cultures were collected. Patient charts were reviewed.

Results

27 patients between ages 5–61 years old were found to have CRPA (only 2 patients < 18 years). 21/27 (77.7%) were male. 21/27 (77.7%) had >40% total body surface area (TBSA) burns, 3/27 (11.1%) had 20–39% TBSA burn and 1/27 (3.7%) had < 20% TBSA burn. 19/27 (70.3%) patients had bacteremia, 6 had respiratory infections with 3 (11.1%) Infection-related Ventilator-Associated Complications (IVAC), 3 had urinary tract infection, and 1 had CRPA from a central venous catheter tip. There were very few co-morbidities. Twenty isolates from 11 different patients were typed and revealed 2 different clonal strains. 5/11 (45%) patients had strain A, and 2/11 (18%) patients had strain B. 3/11 (27.2%) patients had unique strains. CRPA was isolated from 5 different rooms. Water cultures did not reveal CRPA. Failure of hand hygiene, non-adherence to isolation/PPE protocols and clutter were found. Each failure was corrected. No new CRPA patient isolates have been identified.

Conclusion

Transmission was halted by reinforcement of IP measures. Importantly water was not a source of CRPA in this setting and the data suggest transmission due to environmental contamination.

Disclosures

Trish M. Perl, MD; MSc, 7–11: Advisory Board; medimmune: Research Grant
562. Reducing MRSA Bacteremia in Adult Patients through MRSA Decolonization Bundle
Authors: Goldman Erin , LeRose Jennifer , Ramos-Mercado Abdiel , Oring Justin , Chopra Teena
Published: October 2019

Background

Patients colonized with methicillin-resistant Staphylococcus aureus (MRSA) are at an increased risk of developing a subsequent MRSA infection. Moreover, these individuals may serve as an endogenous reservoir to spread the bacteria to other patients. In an attempt to reduce MRSA bacteremia rates, a decolonization protocol was developed and implemented at a tertiary teaching hospital in Detroit, Michigan. In this study, we evaluate the intervention’s impact on community-onset (CO) and hospital onset (HO) MRSA bacteremia rates.

Methods

Infection Control developed an MRSA decolonization bundle for adults that consisted of daily Chlorhexidine gluconate (CHG) bathing and twice-daily nasal swabs with 10% Povidone–iodine (PI) or Nozin for individuals with iodine allergies. Patients with known risk factors for developing an MRSA infection, such as patients residing in an intensive care unit and/or undergoing specified procedure, were prescribed the bundle for their length of stay (Figure 1). Countraindications for nasal decolonization included inhalation injuries, CSF leaks, ENT surgeries, and transphenoidal surgeries. A retrospective chart review of high-risk patients was conducted to determine compliance with the elements of the MRSA decolonization bundle. Rates of CO and HO MRSA bacteremia per 1,000 patient-days were graphed against compliance with bundle elements (2 nasal swabs and 1 CHG bath per day). To quantify the correlation, a linear regression model and the Pearson coefficient was used.

Results

Approximately 2,000 and 1,000 opportunities for nasal decolonization and CHG bathing, respectively, were identified between September 2018 and March 2019. The data suggest a strong correlation between compliance with MRSA decolonization elements and rate of HO MRSA bacteremia (R2 = 0.785) and a moderate association between nasal decolonization and rate of CO bacteremia (R2 = 0.322) (Figures 2 and 3).

Conclusion

The MRSA decolonization bundle of CHG bathing and nasal swabs appears to be an effective strategy to decrease HO MRSA bacteremia rates with higher bundle compliance being associated with lower rates of infection.

Disclosures

All authors: No reported disclosures.
575. Evaluation of Risk Factors and Clinical Outcomes of Patients with Vancomycin-Resistant Enterococcus Infections
Authors: Chauhan Gauri , Vyas Nikunj M , Levin Todd P , Kim Sungwook
Published: October 2019

Background

Vancomycin-resistant Enterococci (VRE) occurs with enhanced frequency in hospitalized patients and are usually associated with poor clinical outcomes. The purpose of this study was to evaluate the risk factors and clinical outcomes of patients with VRE infections.

Methods

This study was an IRB-approved multi-center retrospective chart review conducted at a three-hospital health system between August 2016-November 2018. Inclusion criteria were patients ≥18 years and admitted for ≥24 hours with cultures positive for VRE. Patients pregnant or colonized with VRE were excluded. The primary endpoint was to analyze the association of potential risk factors with all-cause in-hospital mortality (ACM) and 30-day readmission. The subgroup analysis focused on the association of risk factors with VRE bacteremia. The secondary endpoint was to evaluate the impact of different treatment groups of high dose daptomycin (HDD) (≥10 mg/kg/day) vs. low dose daptomycin (LDD) (< 10 mg/kg/day) vs. linezolid (LZD) on ACM and 30-day readmission. Subgroup analysis focused on the difference of length of stay (LOS), length of therapy (LOT), duration of bacteremia (DOB) and clinical success (CS) between the treatment groups.

Results

There were 81 patients included for analysis; overall mortality was observed at 16%. Utilizing multivariate logistic regression analyses, patients presenting from long-term care facilities (LTCF) were found to have increased risk for mortality (OR 4.125, 95% CI 1.149–14.814). No specific risk factors were associated with 30-day readmission. Patients with previous exposure to fluoroquinolones (FQ) and cephalosporins (CPS), nosocomial exposure and history of heart failure (HF) showed association with VRE bacteremia. ACM was similar between HDD vs. LDD vs. LZD (16.7% vs. 15.4% vs. 0%, P = 0.52). No differences were seen between LOS, LOT, CS, and DOB between the groups.

Conclusion

Admission from LTCFs was a risk factor associated with in-hospital mortality in VRE patients. Individuals with history of FQ, CPS and nosocomial exposure as well as history of HF showed increased risk of acquiring VRE bacteremia. There was no difference in ACM, LOS, LOT, and DOB between HDD, LDD and LZD.

Disclosures

All authors: No reported disclosures.
578. Microbiology Laboratory-Driven Standardized Urine Culture Reporting Increases Aminopenicillin Prescribing in Vancomycin-Resistant Enterococci Urinary Infections
Authors: Cheung Genevieve , Javier Diane , Kachouei Farrnam , Pasiliao Roxanne , Ta Michelle , Estevez Dennys , Bolaris Michael , Ha David
Published: October 2019

Background

Vancomycin-resistant Enterococcus (VRE) urinary tract infections (UTI) are traditionally treated with therapies like linezolid or daptomycin. Multiple recent studies have demonstrated that aminopencillins (APs) have equivalent clinical efficacy outcomes as these therapies are able to achieve high urinary drug concentrations and may also have favorable comparative safety profiles and lower costs. Our institution implemented a standardized microbiology report for urine cultures positive for VRE which encouraged prescribing of APs and blinded sensitivity results.

Methods

This was a single-center, retrospective, observational study evaluating the impact of this microbiology report on prescribing outcomes in patients being treated for VRE UTI at a community regional medical center. The study was conducted over 7.5 years with January 2011 to September 2014 representing the pre-intervention cohort and October 2014 to July 2018 representing the post-intervention cohort. Patients were included if they were 18 years or older and received antibiotic therapy for a diagnosed VRE UTI. The primary outcome measure was terminal antibiotic therapy.

Results

Out of 388 patients with VRE positive urine cultures, 102 were included for analysis, 38 in the pre-intervention cohort and 64 in the post-intervention cohort. Cohorts were similar in terms of age, Charlson Comorbidity Index (CCI), β-lactam allergy, ID consultation, and urologic abnormalities. AP prescribing significantly increased from 3% (1/38) in the pre-intervention cohort to 44% (28/64) in the post-intervention cohort both in univariate (OR 29.8, 95% CI 3.7–222.8) and multivariate (OR 38.7, 95% CI 4.8–312.3) analyses. In the post-intervention cohort, age, gender, CCI, β-lactam allergy, and urologic abnormalities were not significantly associated with differences in aminopenicillin prescribing. There was no difference in in-hospital mortality between cohorts.

Conclusion

The results from this study demonstrate that a simple microbiology report for VRE positive urine cultures encouraging AP prescribing is significantly associated with an increase in AP prescribing for diagnosed VRE UTI and should be considered as a supplementary antimicrobial stewardship intervention.

Disclosures

All authors: No reported disclosures.
584. Use of Multi-Disciplinary Prevention Rounds to Reduce Central Line-Associated Bloodstream Infections in a Neonatal Intensive Care Unit
Authors: Linam Matthew , Wright Jessica , Kim Kum , Van Treek Cara , Spafford Patrick
Published: October 2019

Background

Despite successful implementation of evidence-based prevention bundles, central line-associated bloodstream infections (CLABSIs) continue to occur in neonatal intensive care units (NICUs). We hypothesized that multi-disciplinary prevention rounds may be able to further reduce CLABSIs.

Methods

We implemented bedside rounds in a 39-bed tertiary NICU in November 2018 with the focus of reducing CLABSIs. Standardized rounds for all patients with a central venous line (CVL) occurred 2–3 times/week on weekdays during either the day or evening shifts. Rounds included NICU nursing leadership, the Hospital Epidemiologist and the patient’s nurse. Questions focused on the CVL maintenance bundle, reducing line access, and patient-specific CLABSI risk factors. Best practices were reinforced and solutions for identified risk factors were developed. Recommendations were communicated to the physician, as appropriate. Prevention rounds data were collected. Nurses and providers in the NICU were surveyed about their perceptions of the rounds. CLABSIs were identified by Infection Prevention using standard definitions.

Results

The average daily NICU census was 35.6, with an average of 14 patients with CVLs/day. The average duration of rounds was 45 minutes. Recommendations to physicians, such as changing medications from intravenous to oral or line removal, were accepted 85% of the time. 74.5% of nurses and 87.5% of providers thought that prevention rounds had at least some impact on CLABSI prevention. Nurse and provider responses to the perceived impact of CLABSI prevention rounds are in Tables 1 and 2, respectively. In the 12 months prior to starting prevention rounds, the CLABSI rate was 1.53 /1000 line days and the CLABSI rate for the 6 months after starting rounds was 0.99/1,000 line days, a 65% decrease.

Conclusion

CLABSI prevention rounds helped reinforce evidence-based prevention practices, identified patient-specific risk factors and improved physician-nurse communication. CLABSIs in NICU were reduced.

Disclosures

All authors: No reported disclosures.
594. A Multi-Centered Study of the Clinical and Molecular Epidemiology of AmpC Cephalosporinase-Producing (AmpC) Enterobacteriaceae (Ent) Infections in Children
Authors: Medernach Rachel L , Domitrovic T Nicholas , Hayani Karen C , Hujer Andrea M , Qureshi Nadia K , Marshall Steven H , Nguyen David C , Rudin Susan D , Rispens Jared R , Zheng Xiaotian , Weinstein Robert A , Bonomo Robert A , Logan Latania K
Published: October 2019

Background

AmpC producing Ent are an important cause of multidrug-resistant (MDR) infections in pediatrics. Since most AmpC Ent studies have been conducted in adults, we characterized the molecular epidemiology of AmpC Ent strains with transmissible resistance and identified factors associated with AmpC Ent infections in children.

Methods

A case–control study of children (0–18 years) at 4 Chicago hospitals during 2011–18 was performed. Cases were 44 children with infections due to Ent harboring an AmpC as detected by DNA microarray (Check-Points®). PCR, DNA sequencing, MLST, and phylogenetic analyses were performed. Controls (ctrls) were 132 children with expanded-spectrum cephalosporin-susceptible Ent infections matched by age and hospital. Demographics; residence; comorbidities; device, antibiotic, and healthcare exposures were evaluated. Predictors of AmpC Ent infection were assessed by logistic regression.

Results

The median age of AmpC Ent patients was 3.0 years; 50% were male. Of blaAmpC genes, 68% were blaACT/MIR-type and 25% blaCMY-type. Predominant organisms were Enterobacter cloacae (59%) and Escherichia coli (32%); 27% of AmpC E. cloacae belonged to ST114 and 62% co-harbored a blaESBL gene, predominately blaSHV (94%). Most AmpC E. coli strains were unrelated; 71% carried blaCMY, 64% belonged to phylogroups B2/D, and 50% co-harbored blaCTX-M. On bivariate analysis vs. ctrls, AmpC Ent infections were more likely to be respiratory (39% vs. 18%, P < 0.01) and less likely to be urinary tract (41% vs. 67%, P < 0.01) or community-acquired (14% vs. 33%, P < 0.02). By multivariable analysis, children with AmpC Ent infections were more likely to be nonwhite, non-black, non-Hispanic (OR 4.7, CI 1.4–16.1) and have infections due to Enterobacter (OR 7.7, CI 3.5–17). Differences in gender, healthcare location, residential neighborhood, antibiotic exposures, comorbidities, devices or outcomes were not found.

Conclusion

AmpC Ent infections often had healthcare onset, were due to Enterobacter, and occurred in nonwhite, non-black, non-Hispanic children. AmpC Ent commonly co-harbored blaSHV and blaCTX-M ESBL genes which affects therapeutic options and suggests the need for contact precautions. Control of AmpC Ent infections in children will require validating sources and risk factors.

Disclosures

All authors: No reported disclosures.
607. Scope and Predictive Genetic/Phenotypic Signatures of “Bicarbonate [NaHCO3]-Responsivity” and β-Lactam Sensitization among Methicillin-Resistant Staphylococcus aureus (MRSA)
Authors: Ceren. Ersoy Selvi , Zapata-Davila Brianne , Otmishi Mariam , Milan Vanessa , Li Liang , Chambers Henry , Chambers Henry , Xiong Yan , Bayer Arnold
Published: October 2019

Background

Selected MRSA strains become susceptible to β-lactams (e.g., oxacillin [OX]; cefazolin [CFZ]) in vitro when tested in a standard medium (cation-adjusted Mueller–Hinton Broth; CA-MHB) supplemented with NaHCO3 (“NaHCO3-responsivity”). In vivo activity of β-lactams was demonstrated for MRSA strains with this phenotype in a rabbit endocarditis model (Ersoy et al Antimicrob Agents Chemother 2019). The current study was designed to: (i) determine the prevalence of the NaHCO3-responsive phenotype in a large collection of clinical MRSA isolates; and (ii) identify genetic and phenotypic predictors of this phenotype. Methods. 58 recent MRSA bloodstream isolates representing contemporary clonal complex (CC) genotypes were screened for the NaHCO3-responsive phenotype by broth microdilution MICs in CA-MHB, with or without NaHCO3 supplementation (25–44 mM).

Methods

58 recent MRSA bloodstream isolates representing contemporary clonal complex (CC) genotypes were screened for the NaHCO3-responsive phenotype by broth microdilution MICs in CA-MHB, with or without NaHCO3 supplementation (25–44 mM).

Results

43/58 (74.1%) and 21/58 (36.2%) were rendered susceptible to CFZ and OX, respectively, in the presence of NaHCO3; 20 of the 21 OX-susceptible strains were also susceptible to CFZ in the presence of NaHCO3. High baseline β-lactam MICs (i.e., MICs in CA-MHB alone ≥64 µg/mL) was not predictive of NaHCO3 responsivity. The CC8 genotype was correlated with NaHCO3 responsivity for OX, but not CFZ (P < 0.05).

Conclusion

The NaHCO3-responsive phenotype is relatively common for both OX and especially CFZ among clinical MRSA isolates. Identification of specific genetic factors linked to this phenotype remains ongoing. Confirmation in relevant animal models that this phenotype is predictive of β-lactam efficacy in vivo could provide a solid foundation for a paradigm shift in antimicrobial susceptibility testing of MRSA.

Disclosures

All authors: No reported disclosures.
613. Suppression of Daptomycin Resistance Development in Staphylococcus aureus Is a Class Effect of β-Lactams and Is Independent of Daptomycin–β Lactam Synergy
Authors: Miller Christopher R , Dey Somrita , Smolenski Paula , Kulkarni Pushkar S , Baines Sarah L , David. Berti Andrew
Published: October 2019

Background

Previous studies demonstrate that adding oxacillin during daptomycin (DAP) exposure can prevent DAP resistance development in community-acquired (ST8/USA300) MRSA, presumably by preventing mprF mutation. Hospital-acquired strains, such as MRSA sequence types 5 and 239, typically have higher β-lactam (BL) minimum inhibitory concentrations (MICs) than their community-acquired counterparts and are often less toxigenic, more multidrug-resistant and more refractory to primary antistaphylococcal therapies. It is unknown whether DAP resistance prevention occurs in hospital-acquired MRSA lineages or if augmenting DAP therapy with BL antibiotics other than oxacillin would prevent DAP resistance development.

Methods

MRSA ST5/USA100 (D592) and ST239 (JKD6004) differ in the degree to which BL enhances DAP activity. D592 and JKD6004 were passaged in escalating concentrations of DAP in a stepwise fashion in vitro as described previously. Following 28 days of serial passage all replicates were passaged twice on mannitol-salt agar and tested for DAP MIC by Etest. Parallel passages were performed in media supplemented with BL antibiotics. Between-group differences in DAP MIC suppression effectiveness among individual BLs compared with nafcillin was evaluated using Kruskal–Wallis rank-sum testing with Holm-adjusted post-hoc Dunn testing.

Results

Passage of D592 or JKD6004 in DAP resulted in highly DAP-resistant isolates (median ≥256 mg/L, IQR [96,256]). In contrast, when passages were performed in the presence of DAP+BL, DAP resistance development was suppressed. No between-group differences in DAP MIC suppression effectiveness were observed among individual BLs compared with nafcillin. Highly DAP-resistant isolates demonstrated variable collateral susceptibility to BL monotherapy but were frequently susceptible to combination antibiotic exposure.

Conclusion

Addition of β-lactams to DAP can prevent DAP resistance development in vitro in ST5/USA100 and ST239 MRSA, consistent with findings in ST8/USA300 lineages. Furthermore, this ability appears to be a class effect of β-lactam antibiotics and is independent of the extent of DAP-BL synergy. This provides evidence to support the use of BL combination therapy without regard to staphylococcal lineage or specific BL used.

Disclosures

All authors: No reported disclosures.
622. The Accessory Genome in Enterococcal Bacteremia: Results from the Vancomycin-Resistant Enterococcal Bacteremia Outcomes Study (VENOUS)
Authors: Simar Shelby , Hanson Blake , Contreras German , Reyes Katherine , Sahasrabhojane Pranoti V , Misikir Helina , Liu Catherine , Doi Yohei , Barberis Fernanda , Abbo Lilian , Dinh An Q , Spencer Maria , Zervos Marcus , Aitken Samuel L , Aitken Samuel L , van Duin David , Shelburne Samuel A , Shelburne Samuel A , Tran Truc T , Munita Jose M , Arias Cesar A , de los Angeles Spencer Maria
Published: October 2019

Background

Vancomycin-resistant enterococci (VRE) are a major cause of nosocomial bloodstream infections. Enterococci exhibit remarkable genomic plasticity and can recombine through the acquisition of genetic material via mobile genetic elements (MGEs), including resistance genes. The accessory genome plays a major role in the evolution of enterococci within the human host. Thus, dissecting the entire genome (pan-genome) is of paramount importance to characterize the population structure of enterococci causing disease.

Methods

VENOUS is an ongoing prospective, observational study of adults with enterococcal bacteremia. From September 2016 to March 2018, E. faecalis (Efs) and E. faecium (Efm) were collected in 14 hospitals of a single hospital system and a major cancer center in Houston, TX, and a general hospital in Detroit, MI. Short- and long-read genomic sequencing were performed with Illumina MiSeq and Oxford Nanopore Technologies GridION X5, respectively. A proprietary bioinformatics pipeline was utilized for genome assembly and further analyses.

Results

156 Efs and 98 Efm isolates from single patients were analyzed. The average proportion of core genes in each genome was 64.6% (53.0–74.1) and 49.1% (45.2–51.0) for Efs and Efm, respectively. The vanA gene cluster was identified in 5.1% (8/157) of Efs and 57.1% (56/98) of Efm. The plasmid-encoded aac(6′)-Ie-aph(2″)-Ia gene conferring high-level resistance to aminoglycosides was found in 37.6% (59/157) Efs, seven of which also possessed vanA. Long-read sequencing of vanA-harboring plasmids from a subset of VRE revealed that the vanA cluster was carried in plasmids ranging from 31.7 to 132.3 kb. Although the vanA operon was fairly conserved, insertions of MGE were identified in the intergenic regions of vanS/vanH and vanX/vanY. Furthermore, a variety of MGE insertions mediated integration of the vanA operon, including IS1216 and IS256 (figure).

Conclusion

Accessory genes, including AMR genes, comprise a significant proportion of the enterococcal pan-genome, indicating major genetic plasticity within these organisms. Acquired resistance genes seem to have a high degree of recombination and play a substantial role in the expansion of the genomic repertoire in clinical isolates.

Disclosures

Samuel L. Aitken, PharmD, Melinta Therapeutics: Grant/Research Support, Research Grant; Merck, Sharpe, and Dohme: Advisory Board; Shionogi: Advisory Board.
627. Molecular Epidemiology of Daptomycin-resistant Staphylococcus aureus Causing Bloodstream Infections
Authors: Gudipati Smitha , Perri Mary , Couto Natacha , Herc Erica , Zervos Marcus
Published: October 2019

Background

Daptomycin (Dap) has become increasingly important to combat infections caused by Staphylococcus aureus (SA). However, reports of daptomycin nonsusceptible (DNS) SA strains have emerged over the recent years, specifically with alteration of the MprF gene. Mutations in this gene lead to an increase in lysyl-phosphatidyl glycerol production resulting in a lower susceptibility to Dap and cationic antimicrobial peptides. Point mutations in the cls2 gene have also been associated with DNS SA through similar mechanisms of action. This study describes the gene mutations involved in our patients with SA bloodstream infections (BSIs) that developed Dap resistance.

Methods

This is a retrospective study in a tertiary healthcare system in southeast Michigan. SA blood isolates were sequenced through a gene-by-gene approach using Ridom SeqSphere. Charts were reviewed for clinical and laboratory data. Dap minimum inhibitory concentrations (MICs) were determined by E-test. DNS was defined as an MIC > 1.0 µg/mL.

Results

From December 3, 2015 to May 8, 2017, 7 patients were identified with DNS SA BSI. Mean age of the patients was 59 (SD = 13.7) and 86% were male. Mean bacteremia duration was 7 days (SD = 6.3), mean hospital length of stay was 13 days (SD = 9.8), 5 isolates were methicillin-resistant SA, and 2 were methicillin-sensitive SA. When comparing molecular sequencing of all seven patients with their Dap-sensitive strains vs. resistant strains, all patients, except for patient 3, had a point mutation at different allele loci in the MprF gene (Table 1). Additionally, two patients had point mutations in the cls2 gene. When comparing all 27 strains from the seven patients, each cluster was attributed to an individual patient with the exception of cluster one that included patients 5 and 6 suggesting transmission (Figure 1).

Conclusion

DNS SA is infrequent; however, the present study shows that it can emerge both from methicillin-resistant and -susceptible SA most commonly when developing MprF and cls2 gene mutations as seen in our patients. Patient 3 was the exception in our analysis and likely developed DNS SA through another gene mutation. Further studies are necessary to know the frequency of each mutation with all genes associated with DNS SA, and epidemiological risk factors of transmission.

Disclosures

All authors: No reported disclosures
636. Genome Epidemiology of Carbapenem-Resistant Acinetobacter baumannii (CRAb) in the United States
Authors: Iovleva Alina , Mustapha Mustapha , Cober Eric , Richter Sandra S , Arias Cesar A , Jacob Jesse T , Salata Robert , Satlin Michael J , Wong Darren , Bonomo Robert A , van Duin David , Doi Yohei
Published: October 2019

Background

CRAb is a major cause of healthcare-associated infections and is associated with high mortality due to the lack of reliable treatment options. We aimed to elucidate the contemporary population structure of CRAb isolates circulating in US hospitals using whole-genome sequencing (WGS).

Methods

A total of 131 CRAb isolates were identified at four tertiary care medical centers located in Ohio, Pennsylvania, Texas and North Carolina between 2017 and 2018. The genomes were sequenced with Illumina NextSeq and de novo assembled. Sequence types (STs) were identified using the Pasteur Institute MLST scheme. β-Lactamase genes were identified by ResFinder and manually curated.

Results

The 131 isolates belonged to 10 different ST types, including 8 known and 2 novel ones. In this collection, 101 isolates (77.1%) belonged to ST2, the dominant drug-resistant clone in the United States and Europe; 20 isolates belonged to ST499, a less common, but also globally distributed clone. Two isolates each belonged to ST46 and ST79, both common in South America. For the chromosomally encoded blaOXA-51-group genes, 11 variants were identified with blaOXA-66, blaOXA-82, and blaOXA-95 being predominant. For the chromosomally encoded blaADC-group genes, 26 variants were identified, with blaADC-161, blaADC-181, and blaADC-30 being the most common. The most frequent acquired carbapenemase gene was blaOXA-23, which was present in 89 isolates (67.9%). Other acquired blaOXA carbapenemase genes were identified much less frequently and included blaOXA-24, blaOXA-72, blaOXA-207, and blaOXA-237. 17 isolates (13.0%) did not contain any known acquired carbapenemase genes despite resistance to carbapenems.

Conclusion

ST2 is the most prevalent ST type among contemporary CRAb isolates identified in US hospitals, however, new STs are emerging, most notably ST499. Significant diversity was seen among chromosomal blaOXA-51-group carbapenemase, intrinsic blaADC-group cephalosporinase and plasmid-mediated blaOXA-group carbapenemase genes, which likely represented diversification within the STs. Correlations between clinical presentation and outcomes and the genomic features of the infecting isolates are being investigated

Disclosures

All authors: No reported disclosures.
650. Relationship of a Multiplex Molecular Pneumonia Panel (PP) Results with Hospital Outcomes and Clinical Variables
Authors: Rand Kenneth , Beal Stacy , Tremblay Elizabeth , Houck Herbert , Weber Kylie , Sistrom Christopher
Published: October 2019

Background

The Pneumonia Panel (PP) (BioFire Diagnostics, Salt Lake City, UT) detects 15 potentially pathogenic bacteria semiquantitatively (copy #/mL), 8 viruses and 7 resistance genes from the lower respiratory tract in ≈1 hour in the laboratory. Since identification and susceptibility take ≈ 2 days, this rapid result time is very attractive; however, the clinical significance of the PP copy #/mL as well as a predictable group of PP positive but culture negative patients is unknown. We retrospectively studied the relationship of 270 PP results to culture results, clinical data and outcomes.

Methods

Bronchoalveolar lavage fluid (N = 197) and endotracheal aspirates (N = 73) submitted to the UF Health Shands Hospital microbiology laboratory from June-September 2018 were frozen at −70°C, until tested on the PP. Patient data were extracted from the inpatient electronic medical record (Epic).

Results

Of 270 patients tested, 111/270 (41.1%) were PP bacteria negative/culture no growth or normal flora (Group 1), 59/270 (21.9%) were PP positive/culture negative (Group 2), and 100/270 (37.0%) were PP positive/culture positive (Group 3) for at least 1 concordant bacterial potential pathogen. Hospital length of stay (LOS), P = 0.0274, ANOVA; ICU LOS P = 0.0007 and BAL % Polys P < 0.0001 were significantly longer/higher in Group 3 than in Groups 1 and 2 (Table 1). Max daily temp on the day of culture in PP-positive groups 2 and 3 was significantly higher than the PP-negative group 1, P = 0.0260, ANOVA, (Table 1). Age, daily WBC, lowest paO2, max FiO2, % on antibiotics ( ≥80% for all groups), and % with viruses in the PP were not significantly different across groups. When all PP pathogens were grouped by copy # /mL, ICU LOS was significantly longer for 10(7) copies/mL (P = 0.0088), as was BAL % polys (P = 0.0006). Max daily temp was almost significantly higher for PP-positive groups 10(5), 10(6), and 10(7) combined compared with the PP-negative group (Table 2, P = 0.0608).

Conclusion

Hospital LOS was significantly longer and BAL %Polys higher in the bacterial pathogen culture-positive/PP-positive group vs. not positive groups. ICU LOS and BAL %Polys were significantly higher for the PP-positive groups vs. PP negative regardless of culture results. PP results (copy #/mL) independently correlated with outcome and clinical measures.

Disclosures

All authors: No reported disclosures.
652. Impact of FilmArray Meningitis Encephalitis Panel on HSV Testing and Acyclovir Use in Children Beyond the Neonatal Period
Authors: Messacar Kevin , Messacar Kevin , Gaensbauer James , Birkholz Meghan , Levek Claire , Todd James , Tyler Ken , Dominguez Samuel
Published: October 2019

Background

Testing and empiric use of acyclovir for herpes simplex virus (HSV) in children beyond the neonatal period undergoing lumbar puncture for suspected central nervous system (CNS) infection doubled in the past decade, while the incidence of HSV CNS infection is unchanged. A new syndromic multiplex PCR panel (FilmArray Meningitis Encephalitis Panel [MEP]) rapidly detects 14 pathogens in cerebrospinal fluid (CSF), including HSV. The impact of MEP implementation on HSV testing and acyclovir use is unknown.

Methods

We retrospectively compared CSF testing and acyclovir use in the pre-MEP era January 1, 2007–January 22, 2017 to post-implementation era of MEP January 23, 2017–December 31, 2017 amongst children >60 days with a CSF specimen sent to the Children’s Hospital Colorado microbiology laboratory. HSV singleplex PCR testing was available in both the pre-MEP and MEP eras.

Results

The proportion of CSF specimens from children with suspected CNS infection undergoing HSV testing (MEP or HSV PCR) doubled from 25% in the pre-MEP era to 54% in the MEP era (P < 0.01; Figure 1). In the MEP era, HSV testing was conducted by MEP in 96% of cases and HSV PCR in 8% of cases. In both eras, a majority of CSF specimens undergoing HSV testing had no pleocytosis (63% vs. 59%, P = 0.27). Children with negative HSV testing by MEP were less likely to be started on acyclovir than those with negative HSV testing by singleplex PCR (18% vs. 50%, P < 0.01) and, amongst those started, acyclovir was discontinued sooner, after a median 3 vs 5 doses (P = 0.05). Overall, however, a similar proportion of children with suspected CNS infection received acyclovir in the MEP and pre-MEP eras (13% vs. 12%), despite a low rate of HSV positivity (0.5% vs. 0%).

Conclusion

Implementation of MEP for syndromic CSF testing in children >60 days with suspected CNS infection doubled HSV testing without affecting the rate of empiric acyclovir initiation. Patients with negative HSV testing on MEP were less likely to be started on acyclovir, and if started, received fewer doses than those who tested negative on HSV singleplex PCR, likely due to more rapid turnaround time. However, increased MEP testing offset this, suggesting increased use of newer rapid syndromic tests will not cure creeping empiricism. Diagnostic stewardship targeting MEP use toward children with pleocytosis to decrease unnecessary test utilization are warranted.

Disclosures

All authors: No reported disclosures.
668. Quality of Life Changes in Patients with Clostridium difficile Infection (CDI): A Randomized, Double-Blind Trial of Ridinilazole (RDZ) Compared with Vancomycin (VAN)
Authors: Paul Sumita , Vickers Richard , Garey Kevin W
Published: October 2019

Background

C. difficile is the most frequent hospital-acquired bacteria in the United States. CDI is associated with significant morbidity and mortality, and a 46% lower mean EQ-5D index of Health-Related Quality of Life (HRQoL) compared with the general population. However, data on the impact of antibiotic treatment for CDI on HRQoL are lacking.

Methods

RDZ is a novel, narrow-spectrum antibiotic with targeted activity against C. difficile, under development for the treatment of CDI and prevention of recurrence. We evaluated HRQoL prospectively with the EQ-5D-3L in 69 patients enrolled in a Phase 2 randomized, double-blind trial comparing RDZ (n = 36) with VAN (n = 33). EQ-5D-3L was obtained at five time points (baseline, days 5, 10, 12, and 40) with summary index values calculated using US weights (Shaw 2005) evaluating raw scores for mobility, self-care, usual activities, pain/discomfort, and anxiety/depression, and visual analog scale (VAS) scores.

Results

As early as Day 5, CDI patients on RDZ had significant improvements in mean change from baseline in index scores (P = 0.008) and VAS scores (P = 0.01) but no significant improvements were seen in patients on VAN. Time to resolution of diarrhea also occurred sooner with RDZ with a hazard ratio 1.19 in favor of RDZ (90% CI: 0.76, 1.87). Mean changes in index scores in the VAN group took longer to improve significantly compared with baseline and became higher on VAN on Day 12 and Day 40. Treatment-related improvements in pain/discomfort and anxiety/depression are shown in Figures 1 and 2. The mean change from baseline in EQ-5D-3L domains showed the highest (significant) improvements in the pain/discomfort domain for both treatment groups across all time points. However, by Day 40, anxiety/depression improved significantly more with RDZ than with VAN (P = 0.039).

Conclusion

We believe this is the first study to document improvements in HRQoL after antimicrobial treatment for CDI. Patients receiving ridinilazole experienced greater improvements in HRQoL sooner than those on VAN. Anxiety/depression and pain/discomfort improved significantly with treatment. HRQoL should be evaluated in Phase 3 interventional studies for CDI. These results will need to be validated in the ongoing Phase 3 randomized, double-blind, global trials comparing RDZ to VAN for the treatment of CDI.

Disclosures

All authors: No reported disclosures.
674. Pre-Clinical and Phase I Safety Data for Anti-Pseudomonas aeruginosa Human Monoclonal Antibody AR-105
Authors: Loos Andreas , Weich Nadine , Woo Jennifer , Lalonde Guy , Yee Luisa , Dummer Wolfgang , Truong Vu L
Published: October 2019

Background

Anti-bacterial monoclonal antibodies can serve as a new treatment modality for difficult to treat infections. AR-105 is a fully human IgG1 monoclonal antibody (mAb) that binds to an extracellular polysaccharide epitope of Pseudomonas aeruginosa (PA) and was shown to mediate in vitro complement-dependent opsonophagocytic killing. AR-105 is currently being tested in a global Phase 2 clinical trial as an adjunctive treatment to standard of care antibiotics in ventilator-associated pneumonia patients. Here we present pre-clinical efficacy and clinical safety data for AR-105.

Methods

Efficacy in nonclinical studies against PA pneumonia was tested in prophylactic and therapeutic mouse models, either as a stand-alone therapy or in combination with antibiotics. Mice were dosed intranasally or by intravenous infusion with AR-105 post or prior to infection with PA and survival or lung bacteriology were monitored. In a clinical Phase 1 open-label study, 16 healthy volunteers received 2, 8, or 20 mg/kg of AR-105. Adverse events, immunogenicity, and pharmacokinetic (PK) profiles were evaluated for up to 84 days following administration.

Results

In the animal models, AR-105 reduced lung bacterial counts in a dose-dependent manner, and improved survival (80% in the treated group vs. 0% in the control group). Combination of AR-105 with antibiotics was more effective than monotherapy. In the Phase I study, no serious adverse events (AE) were observed in any cohort. Few AE were deemed related to the investigational drug, and all were mild and transient. AR-105 was found to be well tolerated in healthy volunteers with no anti-drug antibodies (ADA) detected. The PK profile was comparable with other human IgG1 mAbs, exhibiting a serum half-life of approximately 20 days.

Conclusion

AR-105 was confirmed to be effective in PA pneumonia animal models, either as stand-alone therapeutic or in combination with antibiotics. In the Phase 1 clinical study, AR-105 was shown to be safe and well-tolerated, with a PK profile similar to that of other IgG1 mAbs. AR-105 is a promising drug candidate for therapy of PA pneumonia.

Disclosures

All authors: No reported disclosures.
681. In vitro Activity of the β-Lactamase Inhibitor QPX7728 in Combination with Several β-Lactams Against Acinetobacter baumannii (AB) and Pseudomonas aeruginosa (PSA)
Authors: Lomovskaya Olga , Lindley Jill , Rubio-Aparicio Debora , Nelson Kirk J , Castanheira Mariana
Published: October 2019

Background

QPX7728 (QPX) is a novel broad-spectrum boron-containing inhibitor of serine- and metallo-β-lactamases (MBLs). We evaluated the in vitro activity of QPX combined with several β-lactams against carbapenem-resistant AB (CRAB) and PSA clinical isolates with varying β-lactam resistance mechanisms.

Methods

A total of 503 CRAB (meropenem [MEM] MIC ≥8 µg/mL) and 762 PSA clinical isolates were tested by the reference broth microdilution method against β-lactams alone and combined with QPX (4 µg/mL and 8 µg/mL). PSA isolates were selected to represent the normal distribution of MEM, ceftazidime–avibactam (CAZ-AVI), and ceftolozane-tazobactam (TOL-TAZ) resistance according to 2017 surveillance data (representative panel). Additionally, 262 PSA isolates that were either nonsusceptible (NS) to MEM (MIC, ≥4 µg/mL) or to TOL-TAZ (MIC, ≥8 µg/mL), or resistant (R) to CAZ-AVI (MIC, ≥16 µg/mL) (challenge panel) were also tested. Within this 262 strain challenge set, 56 strains carried MBLs and the majority also had nonfunctional OprD.

Results

Against CRAB, QPX at 4 and 8 µg/mL increased the potency of all β-lactams tested. MEM-QPX was the most potent combination (table) displaying MIC50/MIC90 at 1/8 and 0.5/4 µg/mL with QPX at fixed 4 and 8 µg/mL, respectively. Susceptibility (S) to MEM was restored in >95% of strains. Against the 500 PSA from the representative panel, S for all QPX combinations was >90%. For the challenge panel, TOL-QPX and piperacillin (PIP)-QPX were the most potent combinations, restoring S in 76–77% of strains. TOL-QPX and MEM-QPX or cefepime (FEP)-QPX restored the MIC values to S rates when applying the CLSI breakpoint for the compound alone (comparison purposes only) in ~90% and ~75% of non-MBL-producing strains, respectively, vs. 60–70% for TOL-TAZ and CAZ-AVI. PIP-QPX reduce the MIC values to S values for PIP-TAZ in ~60% of MBL-producing strains vs. 20–30% and 3–7% for other QPX combinations and non-QPX tested combinations, respectively.

Conclusion

Combinations of QPX with various β-lactam antibiotics displayed potent activity against CRAB and resistant PSA isolates and warrant further investigation.

Disclosures

All authors: No reported disclosures.
683. Assessment of Biofilm Eradication and Cytotoxicity of a Novel Polygalacturonic Acid + Caprylic Acid Wound Ointment Compared with Antiseptic Wound Ointments
Authors: Gerges Bahgat , Reitzel Ruth A , Rosenblatt Joel , Hachem Ray Y , Raad Issam I
Published: October 2019

Background

Antiseptic wound ointments are increasing importance from safety, microbiological and public health points of view. Previously, Rosenblatt et al. (2017) has assessed polygalacturonic acid (PG) + caprylic acid (CAP) solution for biofilm eradication efficacy and cytotoxicity. In this study, we assessed biofilm eradication and cytotoxicity of PG+CAP wound ointment compared with commercially available wound ointment comparators.

Methods

Assessment of antimicrobial efficacy was conducted using a well-established biofilm model. Twenty-four-hour biofilm was formed on silicone discs and exposed wound ointments for 2 hours. Discs were then sonicated and cultured to quantitate any remaining viable biofilm. To assess cytotoxic effects of wound ointments, L-929 fibroblasts were exposed to 2% extracts of each ointment. The trypan exclusion test was used to access cell viability and Alamar blue was used to assess metabolic function. Ointments tested include, PG+CAP formulated in an inert ointment base, benzalkonium chloride quaternary ammonia antiseptic ointment (BZK), polyhexamethylene biguanide (PHMB) antiseptic ointment, and 2-hydroxyethylcellulose + glycerol inert ointment base. Untreated fibroblast cells were used as controls.

Results

Within 2 hours of exposure, PG+CAP ointment able to completely eradicate C. albicans (CA), MDR Pseudomonas aeruginosa (PS), and MRSA. Additionally, PG+CAP was significantly more efficacious than BZK for MRSA (P = 0.002) and PS (P = 0.015) and PHMB for MRSA (P = 0.02).

In the trypan blue exclusion test PG+CAP yielded 96.29% viable cells compared with 77.83% and 83.25%, for the QUAT and PHMB ointments, respectively. Fibroblasts treated with 2% PG+CAP, retained 86.6% of metabolic activity compared with untreated cells while the QUAT and PHMB ointments retained 37.5% and 44.5% metabolic activity, respectively.

Conclusion

PG+CAP has enhanced effects on eradication of biofilm in vitro as well as less toxicity in vitro relative to the antiseptic wound ointments. Further in vivo studies are warranted.

Disclosures

All authors: No reported disclosures.
684. Cardiac Safety in Adults with Community-Acquired Bacterial Pneumonia (CABP) Treated with Lefamulin (LEF) or Moxifloxacin (MOX): Analysis of Lefamulin Evaluation Against Pneumonia (LEAP) 1 and LEAP 2 Study Results
Authors: Darpo Borje , Das Anita F , Stein Daniel , Schranz Jennifer , Gelone Steven P
Published: October 2019

Background

Preclinical data suggest potential effects of LEF on cardiac interval parameters. We therefore assessed LEF cardiac safety from the LEAP 1/2 trials.

Methods

In LEAP 1, PORT III–V patients received LEF 150mg IV q12h for 5–7 days or MOX 400mg IV q24h for 7 days, with optional IV-to-oral switch (600mg LEF q12h or 400 mg MOX q24h). In LEAP 2, PORT II–IV patients received oral LEF 600mg q12h for 5 days or oral MOX 400mg q24h for 7 days. Patients with known QT prolongation or on medication with potential to prolong the QT interval were excluded as per MOX label. After 5 minutes of rest in the supine position, triplicate 12-lead ECGs were obtained within a 5-minute interval at Screening in both studies, on Days 1/3 in LEAP 1 (predose and ≤15 minutes after first IV dose), and on Days 1/4 in LEAP 2 (predose and 1–3 hours after first oral dose), and sent to a central ECG reader for adjudication.

Results

Of 1,282 randomized/treated patients (n = 641/group), 1,274 had baseline (BL) and post-BL ECG data (n = 636 LEF, n = 638 MOX). Consistent with the resolution of infection, ECGs revealed mean reductions of 7–8 beats/minute for both groups in both studies. The largest mean change in QTcF from BL to post-BL was on Day 3 in LEAP 1 (13.6 and 16.4 msec with IV LEF and MOX, respectively) and on Day 4 in LEAP 2 (9.3 and 11.6 msec with oral LEF and MOX, respectively). The proportion of patients meeting potentially important post-BL QTcF values/changes was comparable between treatment groups (table). In the standardized MedDRA query of Torsade de pointes/QT prolongation (broad), the most common treatment-emergent adverse event was ECG QT prolonged (n = 4 LEF, n = 5 MOX). All events were nonserious and mild or moderate in severity. 6 events were considered study drug related (n = 4 LEF, n = 2 MOX). 5 events led to study drug discontinuation (n = 2 LEF, n = 3 MOX). In 2 patients with cardiovascular disease, 1 had ventricular arrhythmia on Day 20 (18 days after last LEF dose) and 1 had cardiac arrest on Day 18 (9 days after last MOX dose); both events were fatal and considered unrelated to study drug by investigator.

Conclusion

Mild prolongation of the QTcF interval was seen with LEF and MOX, with somewhat smaller effects seen with LEF. Given the small effect, LEF is unlikely to pose a clinically significant risk of ventricular proarrhythmia with appropriate precautions and use.

Disclosures

All authors: No reported disclosures.
695. Activity of Imipenem–Relebactam and Ceftolozane–Tazobactam Against a Contemporary Collection of Gram-Negative Bacteria from New York City
Authors: Iregui Alejandro , Khan Zeb , Landman David , Quale John M
Published: October 2019

Background

Carbapenem-resistant Gram-negative bacteria are important nosocomial pathogens, and therapeutic options are often limited.

Methods

Clinical isolates were gathered during a surveillance study in 2017 involving 7 hospitals in Brooklyn, NY. Isolates underwent susceptibility testing using the agar dilution method; for the combination of imipenem-relebactam and ceftolozane-tazobactam, the concentrations of relebactam and tazobactam were fixed at 4 µg/mL. Breakpoints were defined according to CLSI criteria; for imipenem-relebactam, the breakpoint of imipenem was utilized. Isolates were screened by PCR for common carbapenemases.

Results

Overall susceptibility patterns are given in the Table. Of 1805 isolates of E. coli (including 4 with blaKPC), 100% were susceptible to imipenem and imipenem-relebactam. Of 503 isolates of K. pneumoniae (including 19 isolates with blaKPC), all were susceptible to imipenem-relebactam. Of 171 isolates of Enterobacter spp. (including 3 with blaKPC), 100% were susceptible to imipenem-relebactam. Of 260 isolates of P. aeruginosa, 96% were susceptible to imipenem-relebactam and nearly all to ceftolozane-tazobactam. Against A. baumannii, the activity of imipenem-relebactam was the same as imipenem and the ceftolozane-tazobactam MIC was ≤ 4 µg/mL in 65% of isolates.

Conclusion

Imipenem-relebactam possesses promising activity against multidrug-resistant Enterobacteriaceae endemic to New York City. Ceftolozane-tazobactam demonstrated excellent activity against P. aeruginosa, including isolates resistant to carbapenems.

Disclosures

All authors: No reported disclosures.