bluuebunny/crossref_metadata_2025 huggingface dataset:
557. Impact of Heavy Metal Exposure in the Transcriptional Response of Methicillin--Resistant Staphylococcus aureus (MRSA)-USA300 Latin-American Variant (USA300-LV)
Authors: Echeverri Aura M , Rincon Sandra , Solano Sebastian , Rios Rafael , Carvajal Lina P , Arias Cesar A , Diaz Lorena , Reyes Jinnethe
Published: October 2019

Background

USA 300-LV is the predominant MRSA clone in Colombia and contains a genomic island designated “COMER” with genes for copper (Cu) and mercury (Hg) resistance. HM environmental contamination is a serious threat to public health in Colombia and could also influence the selection and evolution of HM resistance genes in MRSA. Here, we investigate the global transcriptomic responses of USA300-LV after exposure to HM under the hypothesis that USA300-LV strains are highly capable of sustaining higher HM concentrations

Methods

We performed comparative RNAseq experiments in USA300-LV clinical strain (CA-MRSA12). Total RNA was isolated in exponential phase in the absence and presence of sub-inhibitory concentrations of Cu and Hg (3 replicates). cDNA libraries were prepared and sequenced on an Illumina platform. Differentially expressed genes (DEG) were calculated by DeSeq2 (p-adjusted value ˂ 0.01) and results on 19 selected genes were confirmed by qRT-PCR.

Results

US300-LV exhibited a larger number of differentially expressed genes when exposed to Hg (n = 114) compared with Cu treatment (n = 16). The most common functional groups of genes upregulated after Hg exposure included those involved in amino acid metabolism (n = 18). In contrast, 45 genes were downregulated after Hg exposure, mostly associated to host immune system defense (n = 11). qRT-PCR confirmed that the most upregulated genes were those involved in murein hydrolase activity, Hg resistance and the transcriptional regulator Cro/CI. Of 9 genes that were downregulated, functional groups included ype VII secretion system, immune modulators and leucocidins. Copper treatment resulted in only 12 genes that were upregulated including those in the COMER element (n = 6), aminoacid metabolism (n = 3), ROS response (n = 1), host immune system defense (n = 1) and unknown function (n = 1). Downregulated genes were those associated to host immune system defense (n = 2), energy generation (n = 1) and unknown function (n = 1).

Conclusion

Differential adaptive responses after exposure to HM in USA300-LV suggest a role in the evolution of antimicrobial resistance and successful spread in the region. Metabolic adaptations involving amino acid metabolism seem to play a role in the evolution of HM resistance in MRSA.

Disclosures

All authors: No reported disclosures.
574. Reporting of Vancomycin-Resistant Enterococcus Bacteremia among National Healthcare Safety Network Acute Care Hospitals
Authors: Tanwar Sukarma S S , Lastinger Lindsey , Bell Jeneita , Bagchi Suparna , Allen-Bridson Katherine , Dudeck Margaret , Edwards Jonathan R
Published: October 2019

Background

The National Healthcare Safety Network’s (NHSN’s) Multidrug-resistant Organism/Clostridioides difficile (MDRO/CDI) Module serves as a surveillance platform for tracking antibiotic-resistant laboratory-identified (LabID) organisms. LabID event surveillance, which does not require submission of clinical data to NHSN, provides proxy measures for MDRO burden. While surveillance of some organisms is federally mandated, these requirements do not extend to vancomycin-resistant Enterococcus (VRE). We sought to describe the extent of acute care hospital (ACH) participation in NHSN VRE surveillance and identify facility-level factors associated with VRE bacteremia. These could explain differences in VRE incidence and be used in preparation for a national risk-adjusted benchmark.

Methods

ACHs that reported at least one month of facility-wide inpatient (FacWideIN) VRE bacteremia LabID Event data to NHSN in 2017 were included in the analysis. LabID events were categorized as healthcare facility-onset (HO), defined as a laboratory result for a specimen collected ≥4 days after admission, or community-onset (CO), defined as a specimen collected < 4 days after admission. Monthly patient day and admission denominators were used to calculate FacWideIN HO incidence and CO prevalence rates. Univariate analyses were performed on facility-level factors from NHSN’s annual hospital survey to assess their relationship with HO VRE bacteremia.

Results

A total of 544 HO VRE bacteremia events were reported by 498 hospitals in 37 states. About 67% of reporting hospitals were located in California. The national rate of HO VRE bacteremia was 0.27 per 10,000 patient-days and the CO VRE bacteremia rate was 0.58 per 10,000 admissions. Major medical school affiliation, hospital type, larger number of beds and ICU beds, longer average length of stay and the presence of an oncology unit were significantly associated with HO VRE bacteremia (Table 1).

Conclusion

Based on the VRE data reported to NHSN, certain facility-level factors may contribute to a higher incidence of HO VRE bacteremia. Future analyses can allow us to determine whether these factors are independently associated with VRE. Risk-adjusted surveillance data can help guide facilities and states to compare their burden of VRE to a national benchmark.

Disclosures

All authors: No reported disclosures.
577. The Role of Healthcare Worker-Mediated Contact Networks in the Transmission of Vancomycin-Resistant Enterococci
Authors: Klein Eili , Hinson Jeremiah , Tseng Katie K , Smith Aria , Toerper Matthew , Amoah Joe , Levin Scott , Milstone Aaron
Published: October 2019

Background

Healthcare workers (HCWs) commonly contact multiple patients daily and serve as an important vector for transmission of pathogens such as vancomycin-resistant enterococci (VRE). Characterizing the HCW-patient network is difficult, which limits understanding of the role of HCWs in the horizontal transmission of pathogens. Electronic health records (EHR) present an opportunity to generate HCW-mediated contact networks and evaluate their impact on transmission.

Methods

Retrospective analysis of patients (PT) admitted to a medical intensive care unit and solid-organ transplant unit between July 2016 and June 2017. Clinical and demographic information, including VRE surveillance swab outcomes, were extracted from the hospital EHR system. PT-HCW-PT connections were defined as HCW contacts with a patient within an hour of another patient. Multi-variable logistic regression was used to analyze factors associated with unit-acquired VRE colonization incidence.

Results

A total of 2,336 patients had a recorded interaction with 4,956 unique HCWs. 146 patients were colonized with VRE on unit-admission, and 29 patients had unit-acquired VRE colonization. HCWs had contact with ~2 (range: 1–23) patients a day and ~6 (range: 1–58) contacts with patients per day (Figure 1), though rates varied by HCW-type. Patients were contacted by ~7 different HCWs resulting in ~28 contacts per day, with nurses being the most common (Figure 2). This resulted in approximately 10 PT-HCW-PT connections per day (range: 1–33) to an average of 3 other patients. After adjusting for known VRE acquisition risk factors, HCW connections to other patients with VRE significantly increased the risk of VRE acquisition (odds ratio = 1.32; 95% CI: 1.20–1.44; Table 1).

Conclusion

Understanding how HCWs connect patients can elucidate how pathogens, such as VRE, spread in the hospital. We demonstrated how EHR data can inform how HCWs connect patients to spread HAIs and the impact of those connections on the spread of VRE. Though EHR data have limitations, as certain activities and contacts are not logged into the system, they provide a scalable and generalizable source for understanding how patients are connected and can be utilized to reduce the spread of nosocomial infections.

Disclosures

All authors: No reported disclosures.
580. Association Between Central Venous Catheter Repair and Bloodstream Infections in a Pediatric Oncology Center
Authors: Barbar Ruba , Hakim Hana , Flynn Patricia , Gaur Aditya H , Wright Darenda , Owings Angie , Su Yin , Tang Li
Published: October 2019

Background

Central venous catheters (CVCs) are important for healthcare delivery in pediatric oncology patients. It is common to repair CVC breakage to prevent replacement. Existing evidence regarding the association between CVC repair and bloodstream infections (BSI) is limited in the general pediatric population and lacking in pediatric oncology patients. We aim at evaluating whether repairing broken CVCs is associated with an increased risk for subsequent BSI in a pediatric oncology center.

Methods

This is a retrospective case-crossover study of pediatric oncology patients with broken CVCs that underwent repair between July 2015 and June 2017. The incidence and characteristics of BSI in the 30-day pre-repair period were compared with those in the 30-day post-repair period. Wilcoxon-Mann–Whitney and Fisher’s Exact tests were used for comparison of continuous and categorical variables, respectively. Univariate logistic regression was used to identify potential risk factors for BSI post CVC repair. Multiple breakages of the same CVC, and BSIs in overlapping observation periods of consecutive breakages are assumed independent.

Results

Sixty-four patients had 99 episodes of CVC breakage/repair in 68 CVCs. Median age (range) at repair was 2.5 (0.15–17.6) years. 48% of CVC breakages occurred in patients with solid tumors, 24% in HSCT recipients, and 19% in patients with leukemia. Only 25% of patients had neutropenia at repair and 14% had CVC occlusion 72 hours prior to breakage. All CVCs were made of silicone and 88% were double lumen external tunneled. First CVC breakage occurred at a median (range) of 130 (2–718) days since insertion, and CVCs were removed at a median (range) of 72.5 (3–753) days from the last repair. End of treatment was the most common cause (43%) for removal. The post-repair incidence of BSI was 4.5 per 1000 line-days compared with a pre-repair incidence of 4.3 (RR= 0.95, 95% CI 0.44, 2.18). There is no statistical difference between the characteristics of the pre-repair and post-repair BSI (Table 1). Figure 1 shows the organisms causing BSI before and after CVC repair. None of the evaluated variables was identified as a significant risk factor for BSI 30 days after CVC repair (Table 2).

Conclusion

Repair of CVC in pediatric oncology patients was not associated with increased risk of BSI.

Disclosures

All authors: No reported disclosures.
588. Are Popliteal Vein PICCs safe for Neonates?
Authors: Lochner Harold J , Rathore Mobeen H
Published: October 2019

Background

Peripherally inserted central catheters (PICCs) have been used as an alternative to central venous catheters ever since first described in 1975. Concerns were raised at our institution about safety of popliteal vein PICCs (P-PICCs) in neonates. There are no published data on the use of P-PICCs in neonates.

Methods

Retrospective review of records of all neonates admitted to an urban, 50-bed, level III Neonatal Intensive Care Unit between January 1, 2016 and December 31, 2018 who had PICCs placed. Records were reviewed for demographic data, number of days with PICC (dwell time), and complications. Complications included infectious such as bacteremia, insertion site infection; and mechanical such as occlusion, leakage, infiltration/edema, inadvertent dislodging, tip malposition, and catheter breakage. Chi-square (C), non-paired independent-samples t test (T), or Mann–Whitney U test (MW) was used for statistical analysis. IRB approval was obtained from University of Florida (teaching institution) and Baptist Health (patient location).

Results

830 PICCs inserted in 522 neonates were identified. 100 (12.0%) were P-PICCs and 730 (88.0%) were NP-PICCs. Of the NP-PICCs, 700/730 (95.8%) were placed in the upper extremities and 30/730 (4.1%) in the lower extremities. P-PICCs were placed in neonates with an average gestational age of 29 weeks vs. 32 weeks for NP-PICCs (P < 0.01, T) and P-PICCs were placed in neonates with average birthweight of 1,210 g vs. 1,840 g for NP-PICCs (P < 0.01, T). The average dwell time for P-PICCs was 15.4 days (range 2–79 days) compared with 14.2 days (range 0–109 days) for NP-PICCs (P = 0.22, MW). Infectious complications occurred in 5/100 (5.0%) of P-PICCs vs. 9/730 (1.23%) of NP-PICCs (P = 0.02, C) and mechanical complications in 13/100 (13%) P-PICCs vs. 75/730 (10.3%) in NP-PICCs (P = 0.39, C).

Conclusion

There was a significant increase in infectious complication rate between P-PICCs and NP-PICCs that necessitated PICC removal. There was a higher rate of complications overall with use of P-PICCs. This may be related to the increased proportion of lower birth weight and gestational age in the P-PICC group compared with the NP-PICC group. We intend to increase the patient numbers by adding data from 2019. Based on our review P-PICCs have increased risk of infectious complication and may not be as safe.

Disclosures

All authors: No reported disclosures.
589. Impact of Parents and the Environment on MRSA Transmission in the Neonatal ICU
Authors: Reich Patrick J , Boyle Mary G , Hogan Patrick G , Gu Hongjie , Xu Yanping , Andersen Heidi , Thompson Ryley , Muenks Carol , Sullivan Melanie , Burnham Carey-Ann D , Haslam David , Fritz Stephanie
Published: October 2019

Background

Methicillin-resistant Staphylococcus aureus (MRSA) colonization predisposes Neonatal Intensive Care Unit (NICU) infants to subsequent infection. Reservoirs for acquisition remain poorly understood, limiting infection prevention efforts to prevent transmission.

Methods

Infants with known MRSA nasal colonization based on hospital surveillance and controls with negative MRSA screening cultures, and their parents, were enrolled in a prospective cohort study. Weekly cultures were collected from infants (4 sites), parents (3 sites), and NICU environmental surfaces (5 sites). Factors associated with MRSA colonization and infection were identified using generalized linear mixed modeling. Whole-genome sequencing (WGS) and pairwise comparisons were performed across entire genomes on 1041 S. aureus isolates using kSNP3. Isolates differing by less than 80 single nucleotide polymorphisms were considered highly related; highly related strains from different sources suggested transmission.

Results

Samples were collected 1–28 (median 7) times from 29 MRSA-colonized infants, 29 controls, 49 mothers, and 21 fathers. Over the study period MRSA colonization was detected in 10 (34%) infants who were not known to be MRSA-colonized based on hospital nasal surveillance cultures. Parent MRSA colonization (OR=11.0; 95% CI: 2.2, 55.0) and environmental MRSA contamination (OR=5.0; 95% CI: 1.6, 15.3) were associated with infant MRSA colonization. Specifically, 87% of infants with an MRSA-colonized parent were MRSA-colonized. MRSA infections occurred in 6 (21%) MRSA-colonized infants and 0 controls (P = 0.05). Infant rectal colonization (OR=15.0; 95% CI 1.6, 140.5) and persistent MRSA colonization (i.e., 3 or more consecutive positive MRSA cultures) (OR=8.4; 95% CI 1.3, 52.5) were associated with MRSA infection. Thirty clusters of highly related isolates were detected, including 12 clusters with highly related isolates from multiple study families (2–6 [median 3] unique families per cluster; Figures 1 and 2).

Conclusion

Our findings suggest MRSA transmission between infants, their parents, and the environment as well as transmission between patients. Future infection prevention efforts should consider parent and environmental reservoirs, as well as the role of extranasal sites of colonization.

Disclosures

All authors: No reported disclosures.
595. Intranasal Mupirocin with Chlorhexidine Bathing has Limited Effectiveness for MRSA Decolonization among Neonates
Authors: Mazade Marc A , Mattern Anne
Published: October 2019

Background

MRSA colonization is a common neonatal problem and is associated with invasive infection. Good hand-washing and contact precautions reduce transmission. However, long-term contact isolation, sometimes for months, causes dissatisfaction among neonatal intensive care unit (NICU) care providers and parents. We examined the effectiveness of MRSA decolonization among neonates over 3 years.

Methods

Our NICU patients are routinely screened for MRSA colonization by PCR testing of nasal and rectal swabs upon admission and every 2 weeks. Patients with a history of MRSA infection or colonization became eligible for MRSA eradication upon reaching 2000g. Our protocol included intranasal muporocin 2% ointment applied to both nares twice daily for 5 days and 2% chlorhexidine wipe bath daily for 7 days. Wipes were used for bathing from the neck down for at least 20 sec per wipe. Two wipes were used for patient’s < 10 kg with the first wipe being used on the neck, chest, arms, and back, and the second wipe being used on the legs, buttocks, and perineum. Patients were excluded from chlorhexidine bathing if they had a known allergy, were < 27 weeks gestation, < 1 week chronological age, receiving phototherapy, or had severe skin disease, open wounds, or burns. Contact isolation was discontinued if 2 sets of nares and rectal PCR swabs 5 days apart were negative and the patient had not been on antibiotics during the screening period. Surveillance MRSA PCR testing continued. Contact isolation was to be re-initiated if subsequent MRSA screening was positive. Patients were not decolonized a second time.

Results

Among infants admitted to the NICU during from 2016 to 2018 MRSA colonization was identified in 102 patients. Fifty-six were noted to have colonization present on admission and 46 were acquired on or after hospital day 3. The decolonization protocol with follow-up screening was completed in 33 infants. Successful decolonization was achieved for only 5 (15%) of infants. There were no adverse reactions noted among neonates and no MRSA decolonized patients reverted to positive by PCR screening while in hospital.

Conclusion

85% of neonates with MRSA failed decolonization. Using mupirocin intranasally and chlorhexidine bathing to decolonize neonates with MRSA was welcomed by staff and families, but was poorly effective.

Disclosures

All authors: No reported disclosures.
597. Cross-resistance of Ceftolozane-Tazobactam and Imipenem-Relebactam Against Clinical P. aeruginosa Isolates: SMART United States 2016–2018
Authors: Lob Sibylle , Kazmierczak Krystyna , DePestel Daryl , Raddatz Janet , Young Katherine , Motyl Mary , Sahm Daniel F
Published: October 2019

Background

Ceftolozane-tazobactam (C/T) is an antipseudomonal cephalosporin combined with a β-lactamase inhibitor. The combination was cleared by FDA and EMA and is approved in the United States and over 60 countries worldwide. Relebactam (REL) is an inhibitor of class A and C β-lactamases that is in clinical development in combination with imipenem (IMI). Using clinical isolates collected in the United States as part of the global SMART surveillance program, we compared the activity of C/T and IMI/REL against P. aeruginosa (PA) isolates.

Methods

In 2016–2018, 29 clinical laboratories from the United States collected up to 250 consecutive, aerobic or facultatively anaerobic, gram-negative pathogens (GNP) from blood, intra-abdominal, urinary, and lower respiratory tract infections. A total of 14,606 GNP were collected, of which 2,774 were PA. MICs were determined using CLSI broth microdilution and interpreted with CLSI 2019 breakpoints; IMI breakpoints were used for IMI/REL.

Results

The activity of C/T and IMI/REL against 2,774 PA is shown (table). Among all PA, 1.8% of isolates were nonsusceptible (NS) to both agents; 4.4% were susceptible (S) to C/T but not to IMI/REL, and 2.9% were susceptible to IMI/REL but not to C/T. Among the subset of isolates collected from patients in ICUs (n = 827), 87.3% were susceptible to both C/T and IMI/REL, 2.7% were nonsusceptible to both agents, 5.8% of isolates were susceptible only to C/T, and 4.2% of isolates were susceptible only to IMI/REL. Among all C/T-NS isolates (all patient locations, n = 132), 61.4% were IMI/REL-S and <30% were susceptible to all other studied β-lactams and fluoroquinolones. Among all IMI/REL-NS isolates (n = 173), 70.5% were C/T-S and <36% were susceptible to all other studied β-lactams and fluoroquinolones. Of the tested agents, only amikacin and colistin exceeded the activity of C/T or IMI/REL against these NS subsets.

Conclusion

Resistance to C/T or IMI/REL was not common among recent clinical isolates of PA collected in the United States, and both agents promise to be important treatment options. A significant proportion of isolates nonsusceptible to one agent was susceptible to the other, especially among isolates from patients in ICUs. The data suggest that susceptibility to both agents should be tested at hospitals.

Disclosures

All authors: No reported disclosures.
603. Identification of a Carbapenemase-Producing, Extensively Drug-Resistant Klebsiella pneumoniae Isolate Carrying a blaNDM-1-Bearing, Hypervirulent Plasmid, United States 2017
Authors: Stanton Richard A , McAllister Gillian A , Bhatnagar Amelia , Karlsson Maria , Brown Allison C , Rasheed James , Elkins Christopher , Halpin Alison L
Published: October 2019

Background

The recent discovery of carbapenemase-producing hypervirulent Klebsiella pneumoniae (CP-HvKP) has signaled the convergence of multidrug resistance and pathogenicity, with the potential for increased mortality. While previous studies of CP-HvKP isolates revealed that most carried carbapenemase genes and hypervirulence elements on separate plasmids, a 2018 report from China confirmed that both could be harbored on a single, hybrid carbapenemase-hypervirulent plasmid. As part of a project sequencing isolates carrying multiple carbapenemase genes identified through CDC’s Antibiotic Resistance Laboratory Network (AR Lab Network), we discovered a blaNDM-1-bearing hypervirulent plasmid found in a KPC- and NDM-positive K. pneumoniae from the United States.

Methods

Antimicrobial susceptibility testing (AST) was performed by reference broth microdilution against 23 agents. Whole-genome sequencing (WGS) was performed on Illumina MiSeq and PacBio RS II platforms.

Results

AST results indicated the isolate was extensively drug-resistant, as it was non-susceptible to at least one agent in all but two drug classes; it was susceptible to only tigecycline and tetracycline. Analysis of WGS data showed the isolate was ST11, the same sequence type that caused a fatal outbreak of CP-HvKP in China in 2016. The genome included two plasmids. The smaller one (129kbp) carried seven antibiotic resistance (AR) genes, including the carbapenemase gene blaKPC-2. The larger plasmid (354kbp) harbored 11 AR genes, including the metallo-β-lactamase gene blaNDM-1, as well as virulence factors iucABCD/iutA, peg-344, rmpA, and rmpA2, which comprise four of the five genes previously identified as predictors of hypervirulence in K. pneumoniae.

Conclusion

This is the first report of a hybrid carbapenemase-hypervirulent plasmid in the United States. The presence of both blaNDM-1 and hypervirulence elements on the same plasmid suggests that the CP-Hv pathotype could spread rapidly through horizontal transfer. This discovery demonstrates the critical role of genomic characterization of emerging resistance and virulence phenotypes by the AR Lab Network as part of US containment efforts.

Disclosures

All authors: No reported disclosures.
604. Gram-Negative Bacilli Carrying Multiple Carbapenemases: the United States, 2012–2018
Authors: Ham David , Mahon Garrett , Bhaurla Sandeep , Horwich-Scholefield Sam , Klein Liore , Dotson Nychie , Rasheed James , Huang Jennifer , Brown Allison C , Kallen Alexander , Walters Maroya S
Published: October 2019

Background

Gram-negative bacilli carrying multiple carbapenemase genes (multi-CP-GNB) present an emerging public health threat; to date, most isolates reported in the literature have been from outside the United States. We reviewed multi-CP-GNB reported to CDC.

Methods

Reports of multi-CP-GNB isolates carrying genes encoding >1 targeted carbapenemases (i.e., KPC, NDM, OXA-48-type, VIM, or IMP) were received from healthcare facilities, health departments, and public health laboratories, and included isolates tested through the AR Laboratory Network (ARLN) beginning in 2017 as well as isolates sent to CDC for reference testing. Epidemiologic data were gathered by health departments during public health investigations.

Results

From October 2012 to November 2018, 111 multi-CP-GNB isolates from 71 patients in 20 states were identified. Two patients had three different multi-CP-GNB and one patient had two different multi-CP-GNB. The majority of cases (76%) were reported in 2017 or later, after ARLN testing began. Among patients with multi-CP-GNB, the most common organism-mechanisms combination was Klebsiella pneumoniae carrying NDM and OXA-48-type enzymes (table). Urine (44%) and rectal (20%) were the most frequent specimen sources for isolates. The median age of patients was 63 years (range 2–89 years); most had specimens collected at acute care hospitals (87%) or post-acute care facilities (9%). Of 50 patients with information available, 37 traveled internationally in the 12 months prior to culture collection. Among these, 88% were hospitalized for ≥1 night while outside the United States with 10 countries reported, of which India was most common (n = 18). All 5 patients with Pseudomonas aeruginosa co-carrying carbapenemases reported recent hospitalization outside the United States.

Conclusion

The multi-CP-GNB reported to CDC include diverse organisms and carbapenemase combinations and often harbored carbapenemases from different β-lactamase classes, which may severely limit treatment options. Healthcare exposures outside the United States were common; providers should ask about this exposure at healthcare admission and, when present, institute interventions to stop transmission in order to slow further US emergence.

Disclosures

All authors: No reported disclosures.
646. Evaluation of the Utility of a New Comprehensive Molecular Assay to Test for the Common Pathogens that Cause Lower Respiratory Tract Infections and its Potential Impact on Antibiotic Therapy
Authors: Tarro Thomas M , Bulter-Wu Susan , Kovacs Andrea , Cielo Mikhaela
Published: October 2019

Background

Lower respiratory tract infection (LRTI) has high mortality among critically ill patients. The current standard of care for diagnosing bacterial causes of LRTI is respiratory culture, which is time consuming and insensitive. The FilmArray Pneumonia Panel (FA-Pneumo) (Biofire Diagnostics, Salt Lake City, UT) is FDA-cleared for the detection of lower respiratory tract pathogens (bacteria, atypical bacteria, and viruses) directly from lower respiratory tract specimens. Here, we evaluated the performance of the FA-Pneumo assay in bronchoalveolar lavage (BAL) samples and assessed its potential impact on antibiotic therapy.

Methods

A total of 61 BAL samples collected for respiratory culture from intensive care unit patients aged 18 years and older who had symptoms consistent with LRTI were included in the study. Remnant BAL samples were tested using the FA-Pneumo and results were compared with standard of care respiratory culture results. We then conducted a chart review to determine the potential impact of FA-Pneumo results on antibiotic therapy.

Results

The results of 48 out of 61 BAL samples (78.7%) were the same when comparing FA-Pneumo with a standard of care respiratory culture. Two patients grew Stenotrophomonas maltophilia and 1 patient grew Achromobacter. Importantly, neither of these organisms is targeted by the FA-Pneumo assay. Three patients (4.9%) had viral LRTI, with 9 patients (14.8%) having bacterial/viral co-infection. A total of six patients with methicillin-susceptible Staphylococcus aureus (MSSA) remained on vancomycin therapy for a median of 1.5 days (range 0–7 days) and all three patients with viral LRTI remained on broad-spectrum antibiotic therapy for a median of 4 days (range 3–13 days). All three patients with ESBL-positive Enterobacteriaceae detected by FA-Pneumo and culture were not started on appropriate antibiotic therapy until >48 hours after the FA-Pneumo would have been resulted.

Conclusion

The FA-Pneumo assay has the potential to lead to earlier discontinuation of vancomycin for patients with MSSA LRTI and earlier broadening of therapy for ESBL LRTI. Providers should be aware of the inability of the FA-Pneumo to detect S. maltophilia and Achromobacter species.

Disclosures

All authors: No reported disclosures.
673. Novel Delayed-Release Formulation of an Oral β-Lactamase Prevents Gut Microbiome Damage and Attenuates Antibiotic Resistance Caused by Oral Amoxicillin/Clavulanate without Interfering with Amoxicillin Systemic Absorption in Dogs
Authors: Connelly Sheila , Furlan-Freguia Christian , Fanelli Brian , Hasan Nur A , Colwell Rita R , Kaleko Michael
Published: October 2019

Background

Exposure of the gut microbiota to antibiotics can alter the composition of the microbiome and lead to the emergence and spread of antibiotic resistance. SYN-004 (ribaxamase) is a clinical-stage β-lactamase intended to degrade certain IV β-lactam antibiotics in the GI tract to preserve the gut microbiome. In a phase 2b clinical study, ribaxamase significantly reduced C. difficile infection in patients treated with IV ceftriaxone. A new delayed-release ribaxamase formulation, SYN-007, intended for use with oral β-lactams, was evaluated in dogs that received oral amoxicillin plus the β-lactamase inhibitor, clavulanate (amox/clav).

Methods

SYN-007 was engineered for release in the lower small intestine, distal to the site of antibiotic absorption. Dogs received amox/clav (40 mg/kg amox/5.7 mg/kg clav, PO, TID) +/- SYN-007 (10 mg, PO, TID) for 16 doses. Amoxicillin serum levels were measured by LC/MS/MS after the first and last doses. DNA, isolated from feces collected before and after antibiotic treatment, was analyzed by whole-genome shotgun sequencing using CosmosID, Inc. metagenomics software.

Results

Serum amoxicillin levels were not significantly different +/- SYN-007 after the first and last doses of amox/clav. Microbiome analyses revealed that amox/clav disrupted the gut microbiome resulting in loss of some species and overgrowth of other taxa. SYN-007 attenuated changes to gut microbiome composition. Amox/clav exposure resulted in the emergence of many, mainly TEM β-lactamase genes that was reduced with SYN-007.

Conclusion

Oral amox/clav disrupted the gut microbiome in dogs and resulted in the emergence of β-lactamase genes. SYN-007 diminished amox/clav-mediated microbiome disruption and attenuated emergence of β-lactamase genes. SYN-007 did not interfere with amox systemic absorption indicating that the β-lactamase was not released in the upper small intestine, the site of oral amoxicillin absorption. Antibiotic inactivation represents a potential new treatment paradigm for preservation of the gut microbiome and reduction of antibiotic resistance. SYN-007 has the potential to expand β-lactamase-mediated microbiome protection to oral as well as IV β-lactam antibiotics.

Disclosures

All authors: No reported disclosures.
686. Evaluation of Contezolid Activity to Anaerobic and Gram-positive-cocci Isolates from a Phase 3 Acute Bacterial Skin and Skin Structure Infection Clinical Trial (MRX-I-06)
Authors: Yang Yang , Zhu Demei
Published: October 2019

Background

Contezolid (MRX-I) is an oxazolidinone in development for the treatment of acute bacterial skin and skin structure infections (ABSSSIs). In this study, in vitro susceptibility (S) for Contezolid and comparator agents for Gram-positive (GP) and anaerobic isolates from Phase 3 ABSSSI clinical trials were determined.

Methods

313 isolates were collected from 65 participated sites and sent to a central laboratory for MIC testing. Clinical isolates included 34 anaerobes (15 Finegoldia magna, 8 Actinomyces spp., 4 Prevotella spp., 3 Propionibacterium avidum, 2 Peptostreptococcus spp., 1 Veillonella spp. and 1 Bacteroides fragilis), 187 S. aureus (59.7%). 12 S. pyogenes, 5 Enterococcus, and 75 other Gram-positive organisms. Broth micro-dilution method was used to determine the MIC of contezolid, linezolid, and other comparators to facultative isolates. Agar dilution was carried out for the anaerobes.

Results

For both 33 MRSA and 154 MSSA MIC50/90 values of contezolid and linezolid were 2 mg/L. One E. faecalis showed decreased susceptibility to oxazolidinones (both MIC = 4). 1 mg/L contezolid and linezolid could inhibit 12 S. pyogenes. 2 mg/L contezolid and linezolid could inhibit 15 Finegoldia magna. 0.5 mg/L contezolid and linezolid could inhibit 8 Actinomyces spp. To one Bacteroides fragili, two Prevotella bivia and one Leuconostoc lactis (Intrinsic resistant to vancomycin) the MIC of contezolid were 4 or 8 mg/L. In general, Contezolid had lower or equal MIC50/90 values against both GP and ANA species compared with linezolid for all organisms.

Conclusion

Contezolid demonstrated potent in vitro antibacterial activity against Gram-positive and anaerobic isolates tested. These data suggest that contezolid might be a beneficial supplement to the arena against MDR Gram-positive infection.

Disclosures

All authors: No reported disclosures.
697. Evaluation of Contezolid Activity to Anaerobic and Gram-positive-cocci Isolates from a Phase 3 Acute Bacterial Skin and Skin Structure Infection Clinical Trial (MRX-I-06)
Authors: Yang Yang , Hu Fupin , Zhu Demei
Published: October 2019

Background

Contezolid (MRX-I) is an oxazolidinone in development for the treatment of acute bacterial skin and skin structure infections (ABSSSIs). In this study, in vitro susceptibility (S) for Contezolid and comparator agents for Gram-positive (GP) and anaerobic isolates from Phase 3 ABSSSI clinical trials were determined.

Methods

313 isolates were collected from 65 participated sites and sent to a central laboratory for MIC testing. Clinical isolates included 34 anaerobes (15 Finegoldia magna, 8 Actinomyces spp., 4 Prevotella spp., 3 Propionibacterium avidum, 2 Peptostreptococcus spp., 1 Veillonella spp. and 1 Bacteroides fragilis), 187 S. aureus (59. 7%). 12 S. pyogenes, 5 Enterococcus and 75 other Gram-positive organisms. Broth micro-dilution method was used to determine the MIC of contezolid, linezolid and other comparators to facultative isolates. Agar dilution was carried out for the anaerobes.

Results

For both 33 MRSA and 154 MSSA MIC50/90 values of contezolid and linezolid were 2 mg/L. One E. faecalis showed decreased susceptibility to oxazolidinones (both MIC = 4). 1 mg/L contezolid and linezolid could inhibit 12 S. pyogenes. 2 mg/L contezolid and linezolid could inhibit 15 Finegoldia magna. 0.5 mg/L contezolid and linezolid could inhibit 8 Actinomyces spp. To one Bacteroides fragili, two Prevotella bivia and one Leuconostoc lactis (Intrinsic resistant to vancomycin) the MIC of contezolid were 4 or 8 mg/L. In general, Contezolid had lower or equal MIC50/90 values against both GP and ANA species compared with linezolid for all organisms.

Conclusion

Contezolid demonstrated potent in vitro antibacterial activity against Gram-positive and anaerobic isolates tested. These data suggest that contezolid might be a beneficial supplement to the arena against MDR Gram-positive infection.

Disclosures

All authors: No reported disclosures.
711. Exebacase (Lysin CF-301) Activity Against Staphylococcus aureus (S. aureus) Isolates From Bacteremic Patients Enrolled in a Phase 2 Study (CF-301-102)
Authors: Anastasiou Diane , Cassino Cara , Schuch Raymond
Published: October 2019

Background

Exebacase (CF-301) is a novel, recombinantly-produced, bacteriophage-derived lysin (cell wall hydrolase) which is the first lysin to report Phase 2 (Ph2) results which demonstrated 42.8% higher clinical responder rates with a single dose of exebacase used in addition to standard of care antibiotics (SOC) vs. SOC alone for the treatment of methicillin-resistant S. aureus (MRSA) bacteremia including endocarditis. We examined exebacase activity by broth microdilution (BMD) against baseline methicillin-sensitive S. aureus (MSSA) and MRSA isolates from each of the 116 participants in the recently complete exebacase”first in-patient’ Ph2 study (NCT03163446).

Methods

Patients with complicated bacteremia or endocarditis caused by S. aureus were enrolled into Study CF-301-102 at study centers in the United States, EU, Latin America, Israel, and Russia from 2017 and 2018. Baseline isolates from blood cultures were collected prior to administration of exebacase. Exebacase MICs against 117 isolates of MSSA (n = 74) and MRSA (n = 43) were determined at a central laboratory using a modified BMD approved by the CLSI for exebacase AST.

Results

The exebacase MICs of baseline patient isolates from the Ph2 study ranged from 0.125 – 2 µg/mL and the MIC50/90 values for all MSSA and MRSA isolates were 0.5/1 µg/mL. Exebacase MICs reported in a recent surveillance study were similar, with MIC50/90 values of 0.5/1 µg/mL. Of the 6 total subjects with EXE MICs of 2, 3 were clinical responders, 2 were indeterminate (not available for assessment), and 1 was a clinical nonresponder at Day 14.

Conclusion

Exebacase was highly active against all baseline S. aureus isolates from blood cultures obtained from bacteremic patients enrolled in the Ph2 study. Based on data from previously presented exposure target attainment animal studies, PK/PD modeling and preliminary nonclinical breakpoint assessments, we expected that strains with MIC values of ≤2 µg/mL will have been susceptible to the Ph2 clinical exebacase dose determined based on target attainment studies under study in Ph2.

Disclosures

All authors: No reported disclosures.
713. Preventive Administration of MEDI6389, a Combination of Monoclonal Antibodies (mAbs) Targeting Alpha-Toxin (AT), Panton-Valentine Leukocidin (PVL), Leukocidin ED (LukED), Gamma-Hemolysin and Clumping Factor A (ClfA), in a Rabbit Model of USA300 MRSA Prosthetic Joint Infection (PJI)
Authors: Yanjie Mao , Valour Florent , Vu Vi Tran Giang , Vu Trang , Delaye Thomas , Quynh Nhu Nguyen Tran , Tkaczyk Christine , Cheng Li , Sellman Bret R , An Diep Binh
Published: October 2019

Background

mAbs targeting staphylococcal virulence factors could represent an interesting preventive strategy in PJI. We evaluate here MEDI6389 compared with isotype-matched control IgG (c-IgG) in a rabbit model of USA300 MRSA PJI.

Methods

Rabbits were randomized for prophylaxis with either c-IgG (n = 13; 30 mg/kg; controls) or MEDI6389 (n = 13; 30 mg/kg of each mAb) administered intravenously 12h before infection. A cemented screw and ultrahigh-molecular-weight polyethylene washer were placed intraarticularly in the external femoral condyle. After suturing the joint capsule and musculocutaneous layers, 300 µL of a standardized bacterial inoculum containing 5 × 105 CFU of a USA300 MRSA clinical isolate were injected intraarticularly. Animals were euthanized on day 8 and the knee joint was harvested for bacteriological analysis (synovial bacterial counts, and enumeration of screw-adherent bacteria after sonication) and histology (conventional pathology, and transmission electron microscopy [TEM] for neutrophils analysis). In vivo observations made on neutrophils were confirmed by TEM analysis of human neutrophils incubated in vitro with purified PVL, LukED, and gamma-hemolysin with or without the corresponding mAb.

Results

In comparison with the control group, the average amount of pus (1.7 ± 1.8 vs. 3.1 ± 1.2 g, P = 0.026) and the number of bacteria in the synovial pus (5.9±1.5 vs. 7.2±1.4 log10 CFU, P = 0.031) and on the screw (2.7 ± 1.5 vs. 4.1 ± 1.6 log10 CFU, P = 0.035) were decreased in animals pretreated by MEDI6389. Conventional pathological examination showed a marked reduction in synovitis of MEDI6389-pretreated animals. TEM of synovitis harvested from infected knee joints of control animals showed significant greater number of abnormal neutrophils that appeared rounded, with condensed nucleus and no granules, compared with those pretreated with MEDI6389 (P = 0.002). This classical leukocidin-induced neutrophilic killing phenotype could be neutralized with anti-leukocidin mAbs using ex vivo human neutrophils incubated with PVL, LukED, HlgAB, or HlgCB.

Conclusion

The preventive administration of MEDI6389 allows a reduction of local inflammation and bacterial burden in this USA300 MRSA rabbit PJI model.

Disclosures

All authors: No reported disclosures.
726. APX001 (Fosmanogepix) Is Effective in an Immunosuppressed Mouse Model of Rhizopus oryzae Infection
Authors: Gebremariam Teklegiorgis , Alkhazraji Sondus , Gu Yiyou , Alqarihi Abdullah , Mamouei Zeinab , Shaw Karen J , Ibrahim Ashraf S
Published: October 2019

Background

Mucormycosis is a life-threatening infection that predominantly occurs in immunocompromised hosts. The antifungal APX001A (manogepix) inhibits Gwt1, an enzyme required for the conserved glycosylphosphatidyl inositol (GPI) post-translational modification in eukaryotes. We previously reported the activity of APX001 (fosmanogepix, the prodrug of APX001A) against Rhizopus delemar (minimum effective concentration [MEC] = 0.25 µg/mL). Here we assessed the activity against R. oryzae, which has an elevated MEC value.

Methods

R. oryzae 99–892 MIC and MEC values were 0.125 µg/mL and 4.0 µg/mL for isavuconazole (ISAV) and APX001A, respectively. ICR mice were immunosuppressed with cyclophosphamide (200 mg/kg) and cortisone acetate (500 mg/kg) on Days -2, +3, and +8 relative to intratracheal infection with 2.5 × 105 cells of R. oryzae 99–892. For survival studies, treatment with 104 mg/kg APX001 was compared with ISAV (110 mg/kg TID). Oral treatment started on Day +1 through Day +7, relative to infection for survival studies, and through Day +4 for tissue fungal burden studies (assessed by conidial equivalent [CE] using qPCR). Placebo mice received vehicle control. To extend the half-life of APX001, mice were administered 50 mg/kg of the cytochrome P450 inhibitor 1-aminobenzotriazole (ABT) 2 h prior to APX001 administration.

Results

APX001 and ISAV equally prolonged median survival time of mice (n = 20) vs. placebo (12 and 14 days for APX001 and ISAV, respectively, vs. 8 days for placebo). Furthermore, APX001 and ISAV treatment both resulted in 30% 21-day survival vs. 0% survival of placebo mice (P < 0.05 by log-rank test). Both drug treatments resulted in ~1.5 log10 reduction in lung and brain CE vs. placebo-treated mice (n = 10, P < 0.005 by Wilcoxon rank-sum test).

Conclusion

Despite a higher MEC value, APX001 showed significant efficacy against R. oryzae that was as protective as ISAV in immunosuppressed mice. Given the previously reported activity of APX001 against a strain of R. delemar with a lower MEC value,APX001 has now been shown to be efficacious against both species of Rhizopus, which together are responsible for ~60–70% of isolates causing lethal mucormycosis. Thus, continued investigation of APX001 against mucormycosis is warranted.

Disclosures

All authors: No reported disclosures.
750. Serious Bacterial Infections: Successful Outpatient Management by Infectious Disease Physicians in Office Infusion Centers
Authors: Adams John S , Metzger Brian S , Mandel Richard M , Sleweon Thomas K , Dretler Robin H , Statner Barry , Bernett Jorge R , Schroeder Claudia P , Hardin Thomas C , Van Anglen Lucinda J
Published: October 2019

Background

Patients with serious bacterial infections (SBI), identified as bone and joint infections (BJI), bacteremia/endocarditis, and central nervous system (CNS) infections are frequently discharged on outpatient parenteral antimicrobial therapy (OPAT). They account for 48% of all infections treated in our network of Infectious Disease (ID) physician office infusion centers (POICs). Care for these patients poses risks and challenges to ensure safe and successful outcomes while avoiding hospitalizations. This study examines clinical outcomes and complications of our SBI patients receiving OPAT in ID POICs.

Methods

All patients were identified with SBI receiving OPAT in 2017 from 14 POICs. A group of 250 patients were randomly selected by incidence of diagnosis and a retrospective chart review performed. Demographics, treatment regimen, clinical outcomes, adverse drug reactions (ADRs) and unplanned hospitalizations during OPAT were collected. Clinical success was defined as clinical cure or improvement at completion of OPAT. Patients were included who were hospitalized for <7 days and subsequently completed OPAT. ADRs leading to hospitalization or discontinuation of OPAT were deemed serious. Descriptive statistics were used for distribution of variables.

Results

SBI patients included BJI (n = 175), bacteremia/endocarditis (n = 60) and CNS infections (n = 15) as described in Table 1. Successful clinical outcomes were reported in 224 patients (89.6%) after a mean duration of OPAT of 32±20 days. Of these, 15 patients (6.7%) were hospitalized during OPAT and returned to the POIC for a successful clinical outcome. Clinical success rates for BJI, bacteremia/endocarditis and CNS infections were 89.1%, 91.6% and 86.7%, respectively. The primary reason for nonfavorable outcomes was worsening of infection (15/26, 58%). Serious ADRs were reported in 12 patients (4.8%) with 6 (2.4%) leading to hospitalization. Unplanned hospitalizations during OPAT occurred in 33 patients (13.2%) with the majority (21/33, 64%) related to disease. ADRs and hospitalizations compare favorably to data previously reported. (Schmidt et al. OFID 16.4, 2017).

Conclusion

Patients with serious bacterial infections had high success rates when treated by an ID physician in infusion centers. Adverse events and unplanned hospitalization rates were low.

Disclosures

All authors: No reported disclosures.
779. Impact of updated IDSA practice guidelines on the treatment of Clostridium difficile infections in the United States
Authors: Clancy Cornelius J , Nguyen Minh-Hong
Published: October 2019

Background

IDSA published updated practice guidelines for C. difficile infections (CDI) in February 2018. Since publication of previous CDI guidelines in2010, randomized clinical trials (RCTs) have demonstrated benefit of oral (po) vancomycin or fidaxomicin over metronidazole in at least some types of CDI. Updated guidelines endorsed vancomycin or fidaxomicin as recommended treatment for initial and recurrent nonfulminant CDI episodes, and vancomycin as treatment for fulminant CDI. We studied the use of po vancomycin, fidaxomicin and metronidazole in the United States before and after publication of updated guidelines.

Methods

We obtained US antibiotic prescription data (IQVIA, Durham, NC) since 2013, and used standard dosing regimens for treatment of initial CDI to estimate numbers of infections treated with different agents. Po vancomycin and fidaxomicin are used exclusively against known or suspected CDI. Metronidazole is used to treat CDI and other infections. IQVIA data do not capture indications for prescriptions.

Results

Treatment courses of po vancomycin and fidaxomicin increased by 45% (n = 126,729 increase) and 44% (n = 11,243 increase), respectively, over the 12 months after publication of the updated CDI guidelines compared with 12 months before publication (Figure, second arrow; Table). Increased use of both agents was evident in the first month after guidelines were published. Over the same 12 month periods, treatment courses of po metronidazole decreased by 3% (190,430 decrease). In comparison, treatment courses of po vancomycin increased by 24% (n = 47,219 increase) over the 12 months after publication of the multi-national PACT study in August 2014 (Figure, first arrow), which demonstrated superiority of vancomycin over metronidazole. Since 2013, there were no significant increases in the use of fidaxomicin until publication of the updated guidelines.

Conclusion

Updated IDSA guidelines have had a major impact on treatment of CDI in the US. RCT data used for guideline updates have been available since 2007–14 and 2011–12 for po vancomycin and fidaxomicin, respectively. IDSA should provide more timely updates to practice guidelines as new data emerge. Annual or bi-annual updates posted in electronic or other nontraditional formats may be more efficient than publishing long-form articles.

Disclosures

All authors: No reported disclosures.