Background: Carbapenem resistance in gram-negative organisms is an important public health problem. The CDC conducted Sentinel surveillance in 2018–2019 to characterize these organisms from 9 facilities in 9 different states. Methods: Carbapenem-resistant Enterobacterales (CRE), Pseudomonas aeruginosa (CRPA), and Acinetobacter spp (CRA) obtained from clinical samples of patients in acute-care or long-term care facilities were submitted to the CDC. Identification was confirmed using matrix-assisted laser desorption ionization time-of-flight (MALDI-TOF), and antimicrobial susceptibility testing (AST) was performed via broth microdilution for 27 antibiotics. All confirmed CRE and CRPA were tested for carbapenemase production (CP) using the modified carbapenem inactivation method (mCIM). The isolates that were mCIM-positive were assessed by real-time PCR for presence of blaKPC, blaNDM, blaVIM, and blaIMP. CP-CRE were also assessed for blaOXA-48-like. All confirmed CRA were tested for the same genes as CRPA and blaOXA-23–like, blaOXA-24/40-like, blaOXA-58–like, and blaOXA-235–like genes. Difficult-to-treat resistance (DTR) was defined as resistance to all β-lactams (excluding newer β-lactam combination agents) and quinolones tested. Results: The CDC confirmed 208 CRE, 161 CRPA, and 94 CRA. Table 1 summarizes AST results for a selection of drugs. We identified 112 (53.8%) mCIM-positive CRE and 6 (3.7%) mCIM-positive CRPA. The PCR results are summarized in Table 2. One mCIM-positive and PCR-negative isolate was positive in a metallo-β-lactamase screen. Conclusions: Resistance among CRE and CRPA to newer β-lactam combination agents was detected. Options for treating CRA are limited. Of 112 CP-CRE, 85.7% harbored blaKPC; CP-CRPA were rare (3.7%); and most CRA harbored blaOXA-23-like (55.3%) or blaOXA-24/40-like (30.9%). Whole-genome sequencing is planned to better understand gene variants, sequence types, and additional resistance markers present among the isolates.

Funding: None

Disclosures: None

Background: Automated testing instruments (ATIs) are commonly used by clinical microbiology laboratories to perform antimicrobial susceptibility testing (AST), whereas public health laboratories may use established reference methods such as broth microdilution (BMD). We investigated discrepancies in carbapenem minimum inhibitory concentrations (MICs) among Enterobacteriaceae tested by clinical laboratory ATIs and by reference BMD at the CDC. Methods: During 2016–2018, we conducted laboratory- and population-based surveillance for carbapenem-resistant Enterobacteriaceae (CRE) through the CDC Emerging Infections Program (EIP) sites (10 sites by 2018). We defined an incident case as the first isolation of Enterobacter spp (E. cloacae complex or E. aerogenes), Escherichia coli, Klebsiella pneumoniae, K. oxytoca, or K. variicola resistant to doripenem, ertapenem, imipenem, or meropenem from normally sterile sites or urine identified from a resident of the EIP catchment area in a 30-day period. Cases had isolates that were determined to be carbapenem-resistant by clinical laboratory ATI MICs (MicroScan, BD Phoenix, or VITEK 2) or by other methods, using current Clinical and Laboratory Standards Institute (CLSI) criteria. A convenience sample of these isolates was tested by reference BMD at the CDC according to CLSI guidelines. Results: Overall, 1,787 isolates from 112 clinical laboratories were tested by BMD at the CDC. Of these, clinical laboratory ATI MIC results were available for 1,638 (91.7%); 855 (52.2%) from 71 clinical laboratories did not confirm as CRE at the CDC. Nonconfirming isolates were tested on either a MicroScan (235 of 462; 50.9%), BD Phoenix (249 of 411; 60.6%), or VITEK 2 (371 of 765; 48.5%). Lack of confirmation was most common among E. coli (62.2% of E. coli isolates tested) and Enterobacter spp (61.4% of Enterobacter isolates tested) (Fig. 1A), and among isolates testing resistant to ertapenem by the clinical laboratory ATI (52.1%, Fig. 1B). Of the 1,388 isolates resistant to ertapenem in the clinical laboratory, 1,006 (72.5%) were resistant only to ertapenem. Of the 855 nonconfirming isolates, 638 (74.6%) were resistant only to ertapenem based on clinical laboratory ATI MICs. Conclusions: Nonconfirming isolates were widespread across laboratories and ATIs. Lack of confirmation was most common among E. coli and Enterobacter spp. Among nonconfirming isolates, most were resistant only to ertapenem. These findings may suggest that ATIs overcall resistance to ertapenem or that isolate transport and storage conditions affect ertapenem resistance. Further investigation into this lack of confirmation is needed, and CRE case identification in public health surveillance may need to account for this phenomenon.

Funding: None

Disclosures: None

Background: The capacity to monitor the emergence of carbapenemase-producing organisms (CPO) is critical in limiting transmission. CPO-colonized patients can be identified by screening rectal specimens for carbapenemase genes and the Cepheid GeneXpert Carba-R (XCR), the only FDA-approved test, is limited to 5 carbapenemase genes and cannot identify the bacterial species. Objective: We describe the development and validation of culture-based methods for the detection of CPO in rectal cultures (RCs) and nonrectal cultures (NRCs) of tracheal aspirate and axilla-groin swabs. Methods: Colonization screening was performed at 3 US healthcare facilities; specimens of RC swabs and NRC ESwabs were collected. Each specimen was inoculated to a MacConkey broth enrichment tube for overnight incubation then were subcultured to MacConkey agar with meropenem and ertapenem 10 µg disks (BEMA) and CHROMagar KPC (KCHR) or CHROMagar Acinetobacter (ACHR). All media were evaluated for the presence of carbapenem-resistant organisms; suspect colonies were screened by real-time PCR for the most common carbapenemase genes. MALDI-TOF was performed for species identification. BEMA, a previously validated method, was the comparator for 52 RCs; clinical culture (CC) served as the comparator method for 66 NRCs. Select CPO-positive and -negative specimens underwent reproducibility testing. Results: Among 56 patients undergoing colonization screening, 12 (21%) carried a CPO. Only 1 patient had CPO solely from RC. Also, 6 patients had both CPO-positive RC and NRC, and 5 patients only had a CPO-positive NRC. Of the latter, 4 had a CPO-positive tracheal specimen, and 1 had a positive culture from both tracheal and axilla-groin specimens. Sensitivity of BEMA (70%) for NRC was lower than for KCHR (96%) and ACHR (88 %) for all specimens. All methods showed a specificity of 100% and reproducibility of 92%. The detected CPO included OXA-23–positive Acinetobacter baumannii, NDM-positive Escherichia coli, KPC-positive Pseudomonas aeruginosa and 4 genera of KPC-positive Enterobacteriaceae. Conclusions:The addition of nonrectal specimens and use of selective media contributed to increased sensitivity and enhanced identification of CPO-colonized patients. Positive cultures were equally distributed among the 3 specimen types. The addition of the nonrectal specimens resulted in the identification of more colonized patients. The culture-based method was successful in detecting an array of different CPOs and target genes, including genes not detected by the Carba-R assay (eg, blaOXA-23-like). Enhanced isolation and characterization of CPOs will be key in aiding epidemiologic investigations and strengthening targeted guidance for containment strategies.

Funding: None

Disclosures: We discuss the drug combination aztreonam-avibactam and acknowledge that this drug combination is not currently FDA approved.

Background: Carbapenemase-producing Enterobacteriaceae (CPE) are a major public health concern because they typically display multidrug resistance and they cause hard-to-treat infections. Organisms harboring metallo-β-lactamases (MBLs) pose a critical challenge in clinical practice because they confer resistance to nearly all β-lactams, including recently approved β-lactam combination agents. A promising new β-lactam-β-lactamase inhibitor combination for treating infections caused by MBL-producing CPE is aztreonam–avibactam. Although clinical trials using aztreonam–avibactam are ongoing, clinicians can administer this combination using 2 US Food and Drug Administration (FDA)–approved drugs: aztreonam and ceftazidime–avibactam. In 2019, the Centers for Disease Control and Prevention (CDC) initiated a pilot program in the Antibiotic Resistance Laboratory Network (AR Lab Network) to address the lack of commercially available antimicrobial susceptibility tests (ASTs) for aztreonam-avibactam by performing broth microdilution (BMD) for this drug combination. We describe the isolates submitted for aztreonam-avibactam AST during the AR Lab Network pilot in 2019. Methods: The AR Lab Network regional laboratories adopted the HP D300e Digital Dispenser to create customized BMD panels for aztreonam–avibactam ASTs. To qualify for aztreonam–avibactam AST, isolates had to be an Enterobacteriaceae displaying nonsusceptibility to all tested β-lactams (including either ceftazidime-avibactam or meropenem-vaborbactam) or confirmed to harbor at least 1 MBL gene (blaVIM, blaNDM, or blaIMP). Regional laboratories confirmed carbapenemase gene(s) using a molecular method. If an MBL gene was confirmed, aztreonam-–avibactam minimum inhibitory concentrations (MICs) were reported back to submitters within 3 working days of receipt. Findings were reported to CDC using a REDCap database. Results: From March through August 2019, aztreonam–avibactam AST was requested for 32 clinical isolates across 16 states. These isolates included 15 Escherichia coli, 12 Klebsiella pneumoniae, 4 Enterobacter cloacae complex, and 1 Proteus mirabilis. Molecular detection identified 27 blaNDM-positive isolates, 2 blaOXA-48-like-positive isolates, and 3 blaOXA-48/blaNDM-positive isolates. Aztreonam-avibactam results were reported for 30 isolates; 5 displayed elevated aztreonam-avibactam MICs of 8/4 µg/mL (n = 4) or 16/4 µg/mL (n = 1). Results for 2 isolates were not reported because the isolates were MBL negative. Aztreonam-avibactam MICs ranged from 0.06/4 µg/mL to 16/4 µg/mL. The MIC50/MIC90 were 0.5/4 µg/mL and 8/4 µg/mL. Conclusions: In the absence of effective FDA-approved treatments and lack of available AST for novel antibiotic combinations, CDC’s provision of AST for aztreonam-avibactam among MBL-producing CPE, offered through the AR Lab Network, helps fill a critical gap to inform patient treatment decisions. To date, our in vitro data suggest that aztreonam–avibactam could be a promising drug combination for use against infections caused by MBL-producing Enterobacteriaceae.

Funding: None

Disclosures: None

Background: Carbapenem-resistant Acinetobacter baumannii (CRAB) are an urgent public health threat because they cause healthcare-associated infections that are difficult to treat and can spread in healthcare environments. Acinetobacter spp may develop resistance to carbapenems through various mechanisms, including decreased permeability, overexpression of efflux pumps, and production of carbapenemases. Carbapenemases found in CRAB commonly belong to the group of carbapenem-hydrolyzing class D β-lactamases, which can be either intrinsic or acquired. The most clinically relevant class D enzymes are the OXA-23-like, OXA-24/40–like, and OXA-58–like because they are commonly plasmid mediated and thereby have the potential for rapid dissemination. We describe the molecular epidemiology of CRAB in the United States using a convenience sample of isolates collected from reference submissions, an isolate-based surveillance system, and the Antibiotic Resistance Laboratory Network (ARLN). Methods: Beginning in August 2017, 7 public health laboratories in the ARLN began testing CRAB isolates submitted by participating sentinel clinical laboratories across their region. Carbapenem-resistant isolates were identified by resistance to imipenem, meropenem, or doripenem. Testing included molecular detection of 4 targeted carbapenemase genes: blaKPC, blaNDM, blaVIM, and blaIMP. Participating labs reported testing results to CDC at least monthly. A separate collection of isolates from CDC reference and surveillance activities between 2013 and 2015 underwent whole-genome sequencing (WGS) to evaluate the presence of acquired carbapenemase genes, including class D OXA-variants. Results: From August 2017 through July 2019, the ARLN tested 2,368 CRAB isolates across 44 states. Only 12 (0.5%) of these harbored a bla- gene: blaKPC (n = 5), blaNDM (n = 5), blaIMP (n = 1), and blaVIM (n = 1). Of 95 reference and surveillance isolates sequenced, none harbored these targeted carbapenemases. However, 69 (73%) harbored at least 1 acquired class D OXA gene; OXA-23 was the most commonly acquired OXA variant (n = 46, 48.4%). Conclusions: Using a multipronged approach, our studies indicate that the presence of class D β-lactamases of the OXA type are common in CRAB among surveillance and reference samples that underwent WGS analysis. Other acquired carbapenemases appear to be rare. To prevent the spread of highly resistant CRAB, particularly those carrying the targeted, emerging carbapenemase genes, continued testing, and rapid infection control are necessary to improve patient safety and maintain situational awareness.

Funding: None

Disclosures: None

Background: Carbapenem-resistant Pseudomonas aeruginosa (CRPA) is a frequent cause of healthcare-associated infections (HAIs). The CDC Emerging Infections Program (EIP) conducted population and laboratory-based surveillance of CRPA in selected areas in 8 states from August 1, 2016, through July 31, 2018. We aimed to describe the molecular epidemiology and mechanisms of resistance of CRPA isolates collected through this surveillance. Methods: We defined a case as the first isolate of P. aeruginosa resistant to imipenem, meropenem, or doripenem from the lower respiratory tract, urine, wounds, or normally sterile sites identified from a resident of the EIP catchment area in a 30-day period; EIP sites submitted a systematic random sample of isolates to CDC for further characterization. Of 1,021 CRPA clinical isolates submitted, 707 have been sequenced to date using an Illumina MiSeq. Sequenced genomes were classified using the 7-gene multilocus sequence typing (MLST) scheme, and a core genome MLST (cgMLST) scheme was used to determine phylogeny. Antimicrobial resistance genes were identified using publicly available databases, and chromosomal mechanisms of carbapenem resistance were determined using previously validated genetic markers. Results: There were 189 sequence types (STs) among the 707 sequenced genomes (Fig. 1). The most frequently occurring were high-risk clones ST235 (8.5%) and ST298 (4.7%), which were found across all EIP sites. Carbapenemase genes were identified in 5 (<1%) isolates. Overall, 95.6% of the isolates had chromosomal mutations associated with carbapenem resistance: 93.2% had porinD-associated mutations that decrease membrane permeability to the drugs; 24.8% had mutations associated with overexpression of the multidrug efflux pump MexAB-OprM; and 22.9% had mutations associated with overexpression of the endogenous β-lactamase ampC. More than 1 such chromosomal resistance mutation type was present in 37.8% of the isolates. Conclusions: The diversity of the sequence types demonstrates that HAIs caused by CRPA can arise from a variety of strains and that high-risk clones are broadly disseminated across the EIP sites but are a minority of CRPA strains overall. Carbapenem resistance in P. aeruginosa was predominantly driven by chromosomal mutations rather than acquired mechanisms (ie, carbapenemases). The diversity of the CRPA isolates and the lack of carbapenemase genes suggest that this ubiquitous pathogen can readily evolve chromosomal resistance mechanisms, but unlike carbapenemases, these cannot be easily spread through horizontal transfer.

Funding: None

Disclosures: None

Background: Carbapenem-resistant Enterobacteriaceae (CRE) represent a significant antibiotic resistance threat, in part because carbapenemase genes can spread on mobile genetic elements. Here, we describe the molecular epidemiology and outcomes of patients with CRE bacteriuria from the same city in a nonoutbreak setting. Methods: The Georgia Emerging Infections Program performs active, population-based CRE surveillance in Atlanta. We studied a cohort of patients with CRE (resistant to all tested third-generation cephalosporins and ≥1 carbapenem, excluding ertapenem) first identified in urine, and not in a prior or simultaneous sterile site, between 2012 and 2015. Whole-genome sequencing (WGS) was performed on a convenience sample. We obtained epidemiologic and outcome data through chart review and Georgia Vital Statistics records (90-day mortality). Using WGS, we created a core-genome alignment-based phylogenetic tree of the Klebsiella pneumoniae isolates and calculated the SNP difference between each sample. Using SAS version 9.4 software, we performed the Fisher exact test and univariable odds ratios (OR) with 95% CI to compare patient isolates with and without a carbapenemase gene. Results: Among 81 patients included, the median age was 68 (IQR, 57–74) years, and most were female (58%), black (60%), and resided in a long-term care facility 4 days prior to culture isolation (53%). Organisms isolated were K. pneumoniae (84%), Escherichia coli (7%), Enterobacter cloacae (7%), and Klebsiella oxytoca (1%). WGS identified at least 1 β-lactamase gene in 91% of the isolates; 85% contained a carbapenemase gene, the most frequent of which was blaKPC-3 (94%). Patients with CRE containing a carbapenemase gene were more likely to be black (OR, 3.7; 95% CI, 1.0–13.8) and to have K. pneumoniae (OR, 8.9; 95% CI, 2.2–35.0). Using a core-genome alignment of 3,708 genes (~63% of the complete genome), we identified a median of 67 (IQR, 23–3,881) SNP differences between each K. pneumoniae isolate. A phylogenetic tree identified clustering around carbapenemase gene and multilocus sequence type (84% were ST 258) but not based on referring laboratory or county of residence (Fig. 1). Although 7% of patients developed an invasive CRE infection within 1 year and 21% died within 90 days, having a carbapenemase gene was not associated with these outcomes. Conclusions: Molecular sequencing of a convenience sample of CRE bacteriuria support K. pneumoniae ST258 harboring blaKPC-3 being distributed throughout the Atlanta area, across the healthcare continuum. Overall mortality was high in this population, but the presence of carbapenemase genes was not associated with worse outcomes.

Funding: None

Disclosures: None

Disclosures: None

Funding: None

The internal stratigraphy of snow and ice as imaged by ground-penetrating radar may serve as a source of information on past accumulation. This study presents results from two ground-based radar surveys conducted in Greenland in 2007 and 2015, respectively. The first survey was conducted during the traverse from the ice-core station NGRIP (North Greenland Ice Core Project) to the ice-core station NEEM (North Greenland Eemian Ice Drilling). The second survey was carried out during the traverse from NEEM to the ice-core station EGRIP (East Greenland Ice Core Project) and then onwards to Summit Station. The total length of the radar profiles is 1427 km. From the radar data, we retrieve the large-scale spatial variation of the accumulation rates in the interior of the ice sheet. The accumulation rates range from 0.11 to 0.26 m a−1 ice equivalent with the lowest values found in the northeastern sector towards EGRIP. We find no evidence of temporal or spatial changes in accumulation rates when comparing the 150-year average accumulation rates with the 321-year average accumulation rates. Comparisons with regional climate models reveal that the models underestimate accumulation rates by up to 35% in northeastern Greenland. Our results serve as a robust baseline to detect present changes in either surface accumulation rates or patterns.

Objective: Mental fatigue occurring after a stroke or traumatic brain injury (TBI) often results in difficulties returning to work and pursuing social activities. No effective treatment of this condition is available today. In this study, we have tested a novel pharmacological strategy using the monoaminergic stabiliser (−)-OSU6162.

Methods: (−)-OSU6162 was given orally for 4 weeks in doses increasing from 15 to 45 mg b.i.d. to 12 patients suffering from mental fatigue, following upon stroke (n=6) or TBI (n=6). (−)-OSU6162 was compared with placebo using a double-blind, randomised cross-over design. Patients included were well rehabilitated physically with no gross impairment in cognitive functions other than those related to the mental fatigue.

Results: (−)-OSU6162 caused a remarkable improvement in mental stamina, as evaluated by a self-assessment scale on mental fatigue. Statistical significance was reached on the primary endpoint (Mental Fatigue Scale). There was a trend towards improvement in the secondary endpoints processing speed and attention. Principal component analysis showed an overall positive treatment effect in 7 of 12 patients. Beneficial responses were seen already during the first few days of active drug treatment. Increasing dosage caused no further improvement. Adverse reactions consisted of short-lasting mild nausea and attenuated appetite. These side effects disappeared upon dose reduction.

Conclusion: The monoaminergic stabiliser (−)-OSU6162 offers promise as a candidate for treatment of mental fatigue after a stroke or TBI.

Physical training, if including specific different training modalities, reduces the fall risk in healthy community-dwelling older people, as does a home hazards modification programme. Vitamin D supplementation in older individuals with low levels of vitamin D, adjustment of psychotropic medication, and structured modification of multi-pharmacy are all drug-focused programmes that reduce the number of falls. Anti-slip shoe devices during icy conditions for older people who walk outdoors and multifaceted podiatry in patients with specific foot disability reduce the fall risk. First eye cataract surgery and pacemakers in patients with cardio-inhibitory carotid sinus hypersensitivity are surgical interventions that reduce the fall risk. Multi-factorial preventive programmes that include training, both individually designed and generally prescribed, also reduce the fall frequency. With this in mind, we ought to initiate fall preventive programmes in older people, especially in high- risk groups, to reduce the number of falls and fallers in society.

This article explores the role of kinship in the Swedish tobacco industry of 1898, making use of rich data that cover the entire industry and include both men and women. The focus is on the role of families in labour recruitment, which is often claimed to have been important. In this case, however, it was not the norm to have a father in the same industry. Occupational following was clearly a gendered phenomenon. To follow in the footsteps of fathers was more common among young men than among other groups of workers, and occupational following was associated with higher earnings for male but not for female workers.

In this study, profiles of temperature and humidity (<250 cm above the road and 5 m into the surroundings) have been used to examine the development of temperature differences in the air layer close to the road. Temperature, humidity and wind profiles were measured, together with net radiation and observations of road surface state, at a test site at Road 45, Surte, Sweden. Measured temperature differences were compared with present weather, preceding weather, surface status, wind direction and other parameters thought to be important for the development of temperature differences. The results showed that large temperature differences (1-3 °C between 250 cm and 10 cm above the road) occurred when there was a high risk of slipperiness caused by hoarfrost, snow or ice on the road. The temperature differences between different levels were associated with the exchange of humidity and temperature between the air layer and the road surface. The 10 cm level reflected the surface processes well. Higher levels were influenced by the surroundings because of turbulence and advection. This study emphasises the need for measurements to be taken at a height and place that reflects the processes at the road surface.