bluuebunny/crossref_metadata_2025 huggingface dataset:
553. Outbreak of Methicillin-Resistant Staphylococcus aureus Associated with Hepatic Artery Infusion Pumps
Authors: Calero Christopher , Usiak Shauna , Aslam Anoshé , Palazzolo Margaret A , McMillen Tracy , Babady Esther , Guest Rebecca , Lucca Bianchi Anabella , Robilotti Elizabeth , Kamboj Mini
Published: October 2019

Background

Device-related infections account for a fourth of all HAIs. Hepatic artery infusion pump (HAIP) devices are used to deliver chemotherapy directly into the hepatic artery. This device is used primarily in patients with colorectal cancer for the management of unresectable hepatic metastases. We describe the infection rates and outbreak management of MRSA-related infections in newly placed HAIPs.

Methods

In December 2018, a cluster of 3 MRSA cases was identified within 15–26 days of HAIP insertion. From January 1, 2017 to December 31, 2018, patients with culture proven SSIs within 30 days of HAIP placement were identified through the infection control database to establish baseline rates. Procedural denominator data were found by querying CPT procedure codes. EMR was reviewed to extract clinical characteristics. In response to the cluster, healthcare personnel (HCP) were screened for MRSA by PCR and environmental cultures performed. PFGE and whole-genome sequencing (WGS) was performed to compare isolates recovered in culture and SNP analysis performed using the BioNumerics software v7.6.

Results

IIn December 2018, 3/15 patients with HAIP procedures developed MRSA infections within 30 days of the procedures (post-op days: 15,16,26). The baseline 30 day SSI rate for HAIP in 2017 was 1.3% (2/160). No infections, prior to the cluster, in 2017–18 were MRSA related. All patients were male, with a median age of 49 years (range: 45–54). Sixty HCP who provided direct care during the peri and early post-operative period for the 3 cases were screened for MRSA carriage; 2/60 (3.3%) were positive. All 56 environmental cultures were negative for MRSA. WGS of the 3 patient samples showed 2/3 samples were identical (1 SNP difference); confirming common source transmission. Only one HCP isolate was available for WGS and shown to be unrelated to the two patient isolates. Both employees underwent decolonization. Review of HAIP handling did not reveal obvious lapses, but mask use and strict hand hygiene were enforced with HCPs. No further infections have been identified in the 76 procedures since the cluster.

Conclusion

WGS confirmed common source transmission between two newly placed HAIP although the definitive source could not be identified. Surveillance and prevention efforts should extend to all types of vascular access devices.

Disclosures

All authors: No reported disclosures.
579. Machine-Learning Based Models for Prediction of Recurrence-free Catheter Retention After ALT Treatment of CLABSI in a Pediatric Population
Authors: Walker Lorne W , Nowalk Andrew J , Visweswaran Shyam
Published: October 2019

Background

Deciding whether to attempt salvage of an infected central venous catheter (CVC) can be challenging. While line removal is the definitive treatment for central-line associated bloodstream infection (CLABSI), salvage may be attempted with systemic antibiotics and antibiotic lock therapy (ALT). Weighing risk and benefit of CVC salvage is limited by uncertainty in the future viability of salvaged CVCs. If a CVC is likely to require subsequent removal (e.g., due to recurrent infection) salvage may not be beneficial, whereas discarding a viable CVC is also not desirable. Here we describe a machine learning approach to predicting outcomes in CVC salvage.

Methods

Episodes of pediatric CLABSI cleared with ALT were identified by retrospective record review between January 1, 2008 and December 31, 2018 and were defined by a single positive central blood culture of a known pathogen or two matching cultures of a possible contaminant. Clearance was defined as 48-hours of negative cultures and relapse was defined as a matching positive blood culture after clearance. Predictive models [logistic regression (LR), random forest (RF), support vector machine (SVM) and an ensemble combining the three] were used to predict recurrence-free CVC retention (RFCR) at various time points using a training and test set approach.

Results

Overall, 712 instances CLABSI cleared with ALT were identified. Demographic and microbiological data are summarized in Tables 1 and 2. Few (8%) instances recurred in the first 28 days. 58% recurred at any time within the study period. Rates of RFCR were 75%, 43%, 22% and 10% at 28, 91, 182 and 365 days. Machine learning (ML) models varied in their ability to predict RFCR (Table 3). RF models performed best overall, although no model performed well at 91 days.

Conclusion

ML models provide an opportunity to augment clinical decision making by learning patterns from data. In this case, estimating the likelihood of useful line retention in the future could help guide informed decisions on salvage vs. removal of infected CVCs. Limitations include the heterogeneity of clinical data and the use of an outcome capturing both clinical decision making (line removal) and infection recurrence. With further model development and prospective validation, practical machine learning models may prove useful to clinicians.

Disclosures

All authors: No reported disclosures.
585. Shifting Focus Toward Healthcare-Associated Bloodstream Infections: Need for More NICU-Specific NHSN Definitions
Authors: Advani Sonali D , Murray Thomas , Bizzarro Matthew
Published: October 2019

Background

Healthcare-associated bloodstream infections (HABSIs) are a significant cause of mortality and morbidity in the neonatal intensive care unit (NICU) population. Our objectives were to review the epidemiology of HABSIs in our NICU and to examine the applicability of National Healthcare Safety Network (NHSN) definitions to the NICU population.

Methods

We performed a retrospective review of all neonates admitted to the 54-bed level IV NICU at Yale-New Haven Children’s Hospital with a HABSI between January 1, 2013 and December 31, 2018. HABSI was defined as a positive blood culture at >72 hours of life growing an organism not considered a contaminant. Clinical definitions per treating NICU team and NHSN site-specific definitions were compared for source attribution using McNemar’s Chi-square test.

Results

We identified 88 HABSIs with an incidence rate of 0.81 per 1,000 patient-days. Only 13% of these were central line-associated bloodstream infections (CLABSIs). Infants with a HABSI had median birth weight and gestational age of 830 grams and 26 weeks, respectively, with a high percentage requiring mechanical ventilation parenteral nutrition and vascular access (Table 1). Sepsis-related mortality was 24%. The majority of HABSIs were caused by gram-positive and gram-negative bacteria (Figure 1). Most were secondary to necrotizing enterocolitis, pneumonia or a source that was not identified (Table 2). NHSN definitions were less likely to identify a source compared with clinical definitions per NICU treating team (P < 0.001, Table 2). Fifty percent of patients without an identified source of infection by NHSN criteria were identified with a Mucosal Barrier Injury (MBI) organism, likely causing bacteremia from gut translocation.

Conclusion

HABSIs occur in premature babies with comorbidities, and are more prevalent than CLABSIs. Gut translocation with MBI organisms may be an important unidentified source of HABSIs in neonates. With the increasing focus on HABSI prevention, there is a need for better NHSN definitions for source attribution of bloodstream infections in neonates.

Disclosures

All authors: No reported disclosures.
591. Mupirocin and Chlorhexidine Resistance in Staphylococcus aureus Isolated from Children in South Korea
Authors: Na Kim Bi , Mi Kang Hyun , Hee Park Sun , Park Joonhong , Han Kang Jin , Kim Jong-Hyun
Published: October 2019

Background

Increasing prevalence of mupirocin-resistant Staphylococcus aureus have been reported, and chlorhexidine resistance has become an issue. This study aimed to investigate the prevalence of mupirocin and chlorhexidine resistance in both colonized and infection causing Staphylococcus aureus in children, and find factors associated with increased virulence.

Methods

Staphylococcus aureus, isolated from children <18 years old admitted at a single center, were collected prospectively from August 2017 to July 2018. The isolates underwent multilocus sequence typing and were screened for genes causing chlorhexidine resistance (qac A/B), quaternary ammonium resistance (smr), mupirocin resistance (ileS mutation, Mup A, MupB), and Pantone Valentine Leucocidin (pvl) toxin.

Results

During the study period, a total of 49 non-duplicate isolates were included, of which 69.4% (n = 34) were Methicillin-resistant Staphylococcus aureus (MRSA). Of the colonizers (n = 25), the most common sequence type was ST 72 (68.0%), whereas among pathogens (n = 24), ST 72 (29.2%) and ST 89 (29.2%) were most prevalent. Pathogens in this study caused abscess formation (n = 3), sepsis (n = 4), and skin infections such as cellulitis and omphalitis (n = 17). Mupirocin resistance was found in 16.0% among colonizers vs. 45.8% among pathogens (P = 0.023). High-level mupirocin resistance was more common (n = 3/25, 12.0%) than low-level mupirocin resistance (n = 1/25, 4.0%) in colonizers, whereas, pathogens had similar rates of low-level (25.0%) and high-level (n = 20.8%) mupirocin resistance. PVL toxin gene was more frequently found in colonizers than pathogens (64.0% vs. 33.3%, P = 0.032), and all isolates had quaternary ammonium resistance genes. Chlorhexidine resistance gene was found in only 3 MRSA isolates colonized in the nares of preterm infants. All were SCCmec type 4, however, two were ST 72, spa type t1054, which had high -level mupirocin resistance and PVL toxin gene.

Conclusion

A PVL toxin gene-positive MRSA which had genes causing mupirocin and chlorhexidine resistance were found in the nasal carriages of preterm infants. These stains may cause failure of MRSA eradication in hospital settings, using conventional methods of nasal mupirocin application and chlorhexidine bathing.

Disclosures

All authors: No reported disclosures.
605. Identification of a Novel CMY-Variant Enzyme in a Clinical Escherichia coli Strain with Treatment-Emergent Ceftazidime–Avibactam Resistance
Authors: Aitken Samuel L , Aitken Samuel L , Endres Bradley T , Khan Ayesha , Shropshire William C , Borjan Jovan , Bhatti Micah M , Sahasrabhojane Pranoti V , Doi Yohei , Shields Ryan K , Shelburne Samuel A , Shelburne Samuel A
Published: October 2019

Background

Ceftazidime–avibactam (CZA) is a novel β-lactam / β-lactamase inhibitor with in vitro activity against multidrug-resistant Gram-negatives, including those harboring CMY-2 enzymes. Treatment-emergent resistance to CZA has been described in KPC-producing Klebsiella pneumoniae but has not been described in non-carbapenemase-producing, carbapenem-resistant Enterobacteriaceae (CRE).

Methods

A patient with an intra-abdominal infection due to a carbapenem-resistant E. coli (ertapenem MIC 16 µg/mL; meropenem MIC 2 µg/mL; CZA MIC 2 µg/mL; carbapenemase negative) was treated with CZA. On day 48 of therapy, a CZA resistant, carbapenem-sensitive E. coli was identified from abdominal drainage (CZA MIC ≥256 µg/mL; meropenem MIC 0.19 µg/mL). Illumina MiSeq whole-genome sequencing (WGS) was performed on both isolates to identify potential resistance mechanisms. The ResFinder database was used to identify known β-lactamase enzymes, and in silico modeling of β-lactamase structure was assessed.

Results

WGS revealed that both isolates were ST410 E. coli, with the sole difference in β-lactam resistance determinants between the two being a novel CMY β-lactamase harbored on an Inc1-type conjugative plasmid in the second isolate. The novel CMY has 4 amino acid substitutions relative to CMY-2: A134E, Q140K, V231S, and N366Y. The V231S substitution is found in CMY-42 and has previously been associated with increased ceftazidime hydrolysis. The remaining three substitutions have not previously been identified. Previous studies have identified that substitutions at position 366 influence the rate of ceftazidime hydrolysis rate. Preliminary protein structure analysis suggests that positions 140 and 366 are in the active site. No other differences in β-lactam resistance determinants were identified between the first and second isolates.

Conclusion

To our knowledge, we have identified the first case of CMY-associated CZA resistance. Given the widespread and transferrable nature of CMY enzymes, this finding raises concern for additional cases of resistance with increasing usage of CZA. Further analysis is needed to identify the mechanism by which this enzyme confers CZA resistance.

Disclosures

Samuel L. Aitken, PharmD, Melinta Therapeutics: Grant/Research Support, Research Grant; Merck, Sharpe, and Dohme: Advisory Board; Shionogi: Advisory Board.
609. Differing Genotypic Contexts Between E. coli and A. baumannii Modulate the Role of blaADC-7 in the Development of Antibiotic Collateral Sensitivity
Authors: McClure Erin , Newman Julia , Krishnan Nikhil , Rutter Joseph , Hujer Andrea M , Adams Mark D , Scott Jacob , Bonomo Robert A
Published: October 2019

Background

Antibiotic resistance is a global health crisis. While persistent drug discovery of novel antibiotics has previously been relied upon to thwart resistance, evolution inevitably perseveres. While genes conferring antibiotic resistance have previously been characterized, it is unclear how varying genetic contexts can change the antibiotic resistance phenotype a given gene confers.

Methods

The DH10B strain of E. coli was transformed with a blaADC-7 plasmid. In 12 evolutionary replicates, the modified E. coli strain and a clinical strain of A. baumannii containing the same resistance gene were passaged daily for 10 days on cefepime gradient agar plates with gradually increasing concentrations of cefepime. MICs of cefepime and a diverse set of 15 other drugs were determined for the parental strains and after the final passage passage. MIC of cefepime after intermediary passages were determined for select replicates. Lastly the blaADC-7 gene after the final passage was sequenced.

Results

At the end of 10 passages, collateral sensitivity in A. baumannii was observed to tigecycline and fosfomycin in 5 and 6 replicates respectively, out of 12 total. 4 out of 12 E. coli replicates displayed collateral sensitivity to minocycline (Figure 1). In the third E. coli replicate, Sanger sequencing revealed a novel S286R mutation in blaADC-7 appearing in passage seven which preceded a several log fold increase in the MIC of cefepime (Figures 2 and 3). No additional mutations were found in the other evolutionary replicates.

Conclusion

Patterns of resistance varied among antibiotics of the same class, (e.g., tetracyclines, fourth-generation cephalosporins) in both E. coli and A. baumannii; however, A. baumannii expressed less widespread collateral resistance than E. coli. A previously undiscovered S286R mutation in blaADC-7 coincided with a pronounced increased in resistance to cefepime. Further studies are required to determine whether this mutation gives rise to a structural change in the protein product. Given that no other mutations were found, resistance to cefepime and subsequent collateral resistance to other antibiotics may have developed due to epigenetic changes or mutations outside the blaADC-7 genes. Indeed, future experiments with whole-genome sequencing may reveal such changes.

Disclosures

All authors: No reported disclosures.
610. Meropenem-vaborbactam (MV) In Vitro Activity Against Carbapenem-Resistant Klebsiella pneumoniae (CRKP) Isolates with Outer Membrane Porin Gene Mutations
Authors: Yasmin Mohamad , Marshall Steven , Jacobs Michael , Rhoads Daniel D , Rojas Laura J , Perez Federico , Bonomo Robert A
Published: October 2019

Background

Vaborbactam is a cyclic boronic acid β-lactamase inhibitor (BLI) developed to potently inhibit Ambler class A&C enzymes, including KPC carbapenemases. Metallo-β-lactamases (MBL) and some Class D oxacillinases (OXA) are not inactivated by vaborbactam. Meropenem-vaborbactam (MV) was recently approved for the treatment of carbapenem-resistant Enterobacteriaceae complicated urinary tract infections. Recent studies have identified outer membrane porin (Ompk35 and -36) mutations in Klebsiella pneumoniae (KP) as a mechanism of decreased susceptibility to MV. We evaluated the activity of MV against a historical cohort of KP clinical isolates with these porin gene mutations.

Methods

WGS of carbapenem-resistant KP clinical isolates was performed and those harboring mutations in Ompk35 or Ompk36 were selected for testing. Strain KP ATCC BAA-1705 was used as a positive control. Meropenem and MV minimum inhibitory concentrations (MIC) were determined by broth microdilution (BMD) in custom 96-well plates (ThermoFisher Scientific) with a constant 8 µg/mL vaborbactam concentration. The MIC of ceftazidime–avibactam (CZA) was determined by standard BMD reference methods and interpreted according to CLSI criteria.

Results

A total of 105 KP isolates with either partial or complete mutations in outer membrane porin genes were included in the analysis. All isolates were resistant to Meropenem. The median MV MIC was 0.03 µg/mL (range, 0.015 to >16 µg/mL). Eleven isolates (10.4%) were resistant to MV. Sixteen additional isolates (16.1%) demonstrated higher than expected MV MICs ranging from 1 to 4 µg/mL. Only 1/11 resistant isolates harbored a gene for MBL production. Gene mutations in blaKPC were not detected. See Table 1 for characteristics of resistant isolates.

Conclusion

Resistance and decreased susceptibility to MV is demonstrated in a historical cohort of KP clinical isolates dating back to 2013. WGS reliably identifies porin variants secondary to gene mutations in Ompk35 and Ompk36 as the underlying mechanism of decreased susceptibility. CZA appears to retain activity against these isolates. Caution should be exercised regarding the empiric use of MV against increasingly resistant KP as a result of non-β-lactamase-mediated mechanisms.

Disclosures

All authors: No reported disclosures.
617. Efficacy of Dimercaptosuccinic Acid (DMSA), a Zinc Chelator, in Combination with Imipenem Against Metallo-β-Lactamase Producing Escherichia coli in a Murine Peritonitis Model
Authors: Cheminet Geoffrey , Nordmann Patrice , Chau Francoise , Kieffer Nicolas , Peoc’h Katell , Massias Laurent , de Lastours Victoire , Fantin Bruno
Published: October 2019

Background

A strategy used by bacterial strains to resist β-lactam antibiotics is the expression of metallo-β-lactamases (MBL) requiring zinc for activity. The use of a zinc chelator may restore carbapenem activity against MBL-producing Enterobacteriaceae. DMSA is a heavy metal chelator approved in humans with a satisfactory safety record. Our objective was to evaluate the activity of DMSA in combination with carbapenems, in vitro and in a fatal murine peritonitis model, against MBL-producing Escherichia coli.

Methods

Isogenic derivatives of wild-type E. coli CFT073 producing the MBL NDM-1, VIM-2, IMP-1, and the serine carbapenemases OXA-48 and KPC-3 were constructed. Minimum inhibitory concentrations (MICs) of imipenem, meropenem, and ertapenem were determined against each strain alone or in combination with DMSA. Mice were infected with E. coli CFT073 or NDM-1 and treated intraperitoneally for 24 hours with imipenem 100 mg/kg every 4 hours, DMSA 200 mg/kg every 4 hours, or both. Mice survival rates and bacterial counts in peritoneal fluid (PF) and spleen were assessed at 24 hours.

Results

In vitro, DMSA in combination with each carbapenem permitted a significant decrease of the MICs against all MBL-producing strains, in a concentration-dependent manner. The maximum effect was found for the NDM-1 strain with a 6- to 8-fold MIC reduction, depending on the carbapenem used. NDM-1 strain became susceptible to carbapenems with concentrations of DMSA ≥6 mM. Increasing zinc concentrations above 1 mg/L (average human plasma concentration) did not alter this effect. No benefit of DMSA was observed against non-MBL strains. In vivo, when used alone, the DMSA regimen was not toxic in uninfected mice and ineffective against NDM-1-infected mice (100% mortality). Combination of imipenem and DMSA significantly reduced bacterial counts in PF and spleen as compared with imipenem alone (P < 0.001), and reduced mortality, although not significantly (11% vs. 37%, respectively, P = 0.12). No benefit of the combination was observed against CFT073.

Conclusion

DMSA is highly effective in vitro in reducing carbapenems MICs against MBL-producing E. coli and appears as a promising strategy in combination with carbapenems for the treatment of NDM-1-related infections.

Disclosures

All authors: No reported disclosures.
619. High Multidrug-Resistant due to TEM and CTX-M-1 Types of Extended-Spectrum β-Lactamase and blaNDM-1 Type Carbapenemase Genes among Clinical Isolates of Gram-Negative Bacilli in Asella, Central Ethiopia
Authors: Tufa Tafese B , André Fuchs , Abdissa Sileshi , Hurissa Zewdu , Martin Orth Hans , Achim Kaasch , Colin Mackenzie , Klaus Pfeffer , Torsten Feldt , Dieter Häussinger
Published: October 2019

Background

Acute infectious diseases and sepsis are among the leading causes of mortality in Ethiopia. The lack of local data concerning causative pathogens and resistance patterns results in suboptimal empirical treatment and unfavorable clinical outcome. The objective of this study was the characterization of bacterial pathogens in hospitalized patients with febrile infections in Central Ethiopia.

Methods

In total, 684 patients ≥1 year of age with fever admitted to the Asella Teaching Hospital from April 2016 to June 2018 were included. Blood and other appropriate clinical specimens were cultured. Susceptibility testing was performed using the Kirby–Bauer method and VITEK2. Confirmation of species identification and identification of resistance genes were conducted using MALDI-ToF and PCR at a microbiology laboratory in Düsseldorf, Germany.

Results

In total, 684 study participants were included; 54% were male and mean age was 26.7 years. Thus, the overall culture positivity rate was 7.5%. Of the 83 cultured organisms, 38(46%) were Gram-negative, 43(52%) Gram-positive, and 2(2%) Candida species. Among the 38 Gram-negative isolates, 16(42%) were E. coli, 15(39%) K. pneumoniae, and 4(11%) P. aeruginosa. Resistance against commonly used antibiotics for Gram-negative at the study site was: piperacillin/tazobactam 48%(13), ampicillin/sulbactam 93% (25), cefotaxime 89%(24), ceftazidime 74%(20), Cefipime 74%(20), meropenem 7%(2), amikacin 4% (1) and gentamicin 56%(15). Of 27 Gram-negative available for resistance-gene detection, blaNDM-1 was detected in one K. pneumoniae isolate and blaNDM-1 plus blaOXA-51 in A. baumannii. 81%(22/27) of the Gram-negative rods were confirmed to contain ESBL-genes as follows: TEM 17(77%), CTX-M-1-group 15(68%), SHV-6(27%) and CTX-M-9-group 2(9%). Among isolated S.aureus, 1(5%) was confirmed to be Methicillin-resistant S. aureus.

Conclusion

We found a high prevalence (81%) of ESBL-producing bacteria and 7.4% carbapenem resistance at the study site. More than half of Gram-negative isolates had two or more mobile resistance genes. These findings warrant the need for local national multidrug-resistant surveillance. Strengthening of antimicrobial stewardship programs is needed in order to face the threat of multidrug-resistant bacteria.

Disclosures

All authors: No reported disclosures.
620. Sub-MIC Concentrations of Levofloxacin and Delafloxacin Enhance Staphylococcus aureus Biofilm Formation: Significance of Maximizing Exposure
Authors: Bodo Emily C , Daffinee Kathryn E , LaPlante Kerry
Published: October 2019

Background

Fluoroquinolones are utilized in Staphylococcal prosthetic joint infections due to their anti-biofilm activity. When antibiotic dosing is not optimized or antibiotics do not reach the site of infection, additional virulence factors may upregulate. We aimed to determine whether exposure to sub-MIC concentrations of levofloxacin and delafloxacin affect biofilm formation in Staphylococcus aureus.

Methods

This study utilized 50 diverse methicillin-susceptible S. aureus (MSSA) clinical isolates collected between 2004 and 2018. Sources included blood, skin/tissue, bone, and joint fluid. Minimum inhibitory concentrations and minimum bactericidal concentrations were identified according to CLSI. Biofilm assays were conducted as previously described by our program. Biofilm quantification was categorized as strong (OD570 ≥ 2), moderate (OD570 ≥ 1 and < 2), or weak (OD570 < 1). Prevention assays were conducted with the addition of increasing concentrations of delafloxacin or levofloxacin. We evaluated the amount of isolates that demonstrated increased biofilm formation in the presence of sub-MIC concentrations and extent of biofilm enhancement. Percent change was calculated between OD570 of the isolate growth control without antibiotic exposure and peak biofilm OD570 when exposed to the antibiotic.

Results

Of the 50 MSSA isolates, 14 (28%) exhibited moderate/strong formation and 36 (32%) exhibited weak biofilm formation. 52% and 58% of the isolates demonstrated a ≥50% increase in formation when exposed to sub-MIC concentrations of delafloxacin and levofloxacin, respectively. None of the strong biofilm formers demonstrated a ≥50% peak increase in formation when exposed to the antibiotics. Of the isolates that demonstrated a ≥50% peak increase, the average percent change was 267% (±29) with levofloxacin and 258% (±33) with delafloxacin.

Conclusion

Sub-MIC concentrations of delafloxacin and levofloxacin increased biofilm formation in S. aureus isolates that normally exhibit weak or moderate biofilm formation when not in the presence of antibiotics. Maintaining appropriate fluoroquinolone concentrations at the site of action is critical in preventing enhancement of biofilm formation. Further research is needed to identify the mechanism behind this increase.

Disclosures

All authors: No reported disclosures.
621. In vitro Ceftazidime: Avibactam Resistance in Carbapenem-Resistant Enterobacteriaceae Isolates
Authors: Belal Maymonah , Villasis Lori , Diago-Navarro Elizabeth , Motley Michael , Young; Eric Spitzer Allen , Fries Bettina C , Monteforte Melinda
Published: October 2019

Background

Ceftazidime–avibactam (CAZ-AVI) is a new antibiotic with activity against many Carbapenem-resistant Enterobacteriaceae (CRE). Although CAZ-AVI resistance in CRE has been reported, it is not consistently assessed. Our study aimed to assess the prevalence of CAZ-AVI resistance in CRE isolated from patients with and without prior exposure to CAZ-AVI.

Methods

We tested 116 CRE isolates for CAZ-AVI resistance by Kirby–Bauer (KB) disk diffusion susceptibility. Resistant isolates were verified by repeat KB and E-test performed by the Stony Brook Hospital laboratory. The blaKPC gene of resistant strains was amplified by PCR and sequenced. Patient data were used to determine whether patients were colonized or infected, and whether they were exposed to CAZ-AVI.

Results

Of the 116 CRE isolates from 86 patients (96 encounters), 50% were Klebsiella species, 23.2% were Enterobacter species, 10.3% Escherichia coli and 16.5% other CRE. They were recovered from colonized (37%) and infected (63%) patients of which 18% were treated with CAZ-AVI during their hospitalizations (median duration of therapy, 6 days). Two CRE isolates (1.7%) were found to be resistant on repeated testing. One isolate was K. pneumoniae derived from the sputum of a patient diagnosed with ventilator-associated pneumonia who received 40 days of CAZ-AVI therapy prior to isolation of the resistant isolate (KB diameter 20 mm, MIC > 512 μg/mL by E-Test). Sequencing of the strain’s blaKPC3 gene revealed a previously described Ambler-position D179Y mutation that has been shown to convey resistance. The second CAZ-AVI-resistant K. pneumoniae (KB diameter 19 mm, MIC 64 μg/mL by E-test) was isolated from the urine of a colonized patient naïve to CAZ-AVI therapy. The strain’s blaKPC10 gene had no mutations.

Conclusion

In our strain collection, the rate of resistance to CAZ-AVI remains low <2%. Although we found one mutation (D179Y) previously linked to CAZ-AVI resistance we also discovered one K. pneumoniae isolate with in vitro resistance to CAZ-AVI that did not exhibit any blaKPC mutations conveying CAZ-AVI resistance. Interestingly, this strain was derived from a patient with no prior CAZ-AVI exposure. Whole-genome sequencing will be performed to identify other genes or mutations that may confer resistance.

Disclosures

All authors: No reported disclosures.
623. Antimicrobial Resistance in Non-Typhoidal Salmonella from Retail Poultry Meat by Antibiotic Usage-related Production Claims—Pennsylvania, 2008–2017
Authors: Yin Xin , M’ikanatha Nkuchia M , Dettinger Lisa , Johnston Melinda , Eckroth William , Husband Brigitte , Tait James , Nyirabahizi Epiphanie , Tate Heather
Published: October 2019

Background

Antimicrobial-resistant (AMR) nontyphoidal Salmonella infections are a public health concern. Injudicious use of antimicrobials fuels emergence of resistance. The National Antimicrobial Resistance Monitoring System (NARMS) tracks AMR in Salmonella from humans, animals and foods. There is limited evidence regarding antimicrobial use in food animals and AMR bacteria in retail meat.

Methods

We reviewed antimicrobial susceptibility and whole-genome sequencing data from 320 Salmonella isolated from poultry meat in Pennsylvania as part of NARMS activities. Salmonella strains were isolated from 3,481 samples purchased from randomly selected retail outlets during 2008–2017. Antibiotic usage claims on meat packages were used to compare AMR Salmonella from conventional and antibiotic-free/organic (Abx-free) samples. Genetic mechanisms for AMR were investigated in a subset of isolates.

Results

The prevalence of Salmonella in conventional poultry meat 10.2% (280/2,733) was significantly higher than the prevalence in poultry meat labeled as Abx-free (5.3%, 40/748; P < 0.0001). Salmonella from conventional poultry meat was more likely to be resistant to 3 or more drugs (55.0%, 154/280) compared with poultry meat labeled as Abx-free (27.5%, 11/40; P = 0.0011). Salmonella from conventional poultry exhibited significantly higher resistance to 4 drug classes including β-lactams (P = 0.006) (figure). One hundred isolates from conventional poultry meat and 8 isolates from antibiotic-free/organic samples harbored a gene conferring resistance to the β-lactam class; 24.3% (68/280) of isolates from conventional and 7.5% (3/40) of isolates from Abx-free samples (P = 0.0145) contained the extended-spectrum β-lactamase (ESBL) gene blaCMY-2.

Conclusion

Meat samples from conventionally-raised poultry were more likely to be contaminated with AMR Salmonella strains and have genes that reduce the effectiveness of antimicrobial drugs recommended for treatment of severe infections. Contamination of poultry with AMR Salmonella strains is concerning as is the presence of genes that decrease the power of critical antibiotics such as β-lactams. These findings highlight the importance of judicious use of antibiotics in food-producing animals.

Disclosures

All authors: No reported disclosures.
625. Genomic Epidemiology of Carbapenem-Resistant Enterobacteriaceae from Colombia: A Prospective Multicenter Study
Authors: Reyes Jinnethe , Diaz Lorena , Carvajal Lina P , Rios Rafael , Millan Lina V , Echeverri Aura M , Hernandez Angie K , Vargas Sandra , Salcedo Soraya , Marin Adriana , Mora Laura , Ordonez Diaz Karen M , Cristancho Quintero Edilberto , Valderrama Sandra , Elena Ariza Beatriz , Cortes Gloria , Rojas Laura J , Chambers Henry F , Fowler Vance G , Kreiswirth Barry , Virginia Villegas Maria , Bonomo Robert A , Hanson Blake , van Duin David , Arias Cesar A
Published: October 2019

Background

Carbapenem-resistant Enterobacteriaceae (CRE) is a serious public health threat. A major epidemic of carbapenemase-producing Klebsiella pneumoniae has occurred in Colombia through complex mechanisms of blaKPC dissemination. In the framework of a prospective, observational cohort study (CRACKLE-2), we aimed to characterize the genomic epidemiology of CRE circulating in Colombia.

Methods

We performed whole-genome sequencing of 52 isolates collected from the same number of patients (July 2017–April 2018) in 5 Colombian hospitals. Species confirmation and sequence type were determined using Strain Seeker and MLST database. Resistance genes were detected using ResFinder and CARD databases. Phylogenetic reconstruction included additional 108 isolates of carbapenem-resistant K. pneumoniae from a previous study.

Results

K. pneumoniae (36%), Escherichia coli (17%), and Enterobacter cloacae complex(17%) were the most frequent species. Genes conferring resistance to carbapenems were detected in 93% of isolates. blaKPC-2/3,blaNDM-1 andblaVIM-2/24 were identified in 81%, 15%, and 5% of isolates, respectively. Phylogenetic reconstructions of K. pneumoniae showed that clonal group 258 (CG258) were the predominant genetic lineage (Figure 1). Among CG258, ST11 was the most common comprising ca. 26% of isolates. Of note, ST11 had been extremely rare in previous surveillance studies in Colombia. The non-CG258 were from 9 different STs and exhibited high genomic diversity. Among E. coli isolates 33% belonged to the high-risk clone ST131 harboring blaKPC-2 and we detected both blaKPC-2 and blaVIM-24 in 1 E. coli ST131 isolate. ST510 E. cloacae complex harboring blaKPC-2 was the most common (44%) lineage.

Conclusion

K. pneumoniae and E. coli are the most frequent CRE isolated from patients in Colombian hospitals. Dissemination of blaKPC through horizontal gene transfer to several species of Enterobacteriaceae continues to be a common mechanism of spread. Although KPC continues to be the most common carbapenemase, a rise in high-risk clonal lineages harboring metallo-carbapenemases, in particular NDM-1 is worrisome. Our results indicate emergence of virulent genetic lineages of K. pneumoniae ST11 and E. coli ST131 carrying carbapenemases in Colombia.

Disclosures

All authors: No reported disclosures.
687. In vitro Activity of a New Generation Oxopyrazole Antibiotic Against Acinetobacter spp.
Authors: Goldberg Joel , Bethel Christopher , Hujer Andrea M , Hujer Kristine , Marshall Steven , Papp-Wallace Krisztina M , Perez Federico , Spencer Elizabeth , Hoyer Denton , Plummer Mark , Bonomo Robert A
Published: October 2019

Background

Acinetobacter spp. resistant to common antibiotics have become a worrying cause of hospital-acquired infections and represent a critical need for innovative antibacterial development. New oxopyrazole agents targeting penicillin-binding proteins (PBPs) based on a non-β-lactam core and incorporating a siderophore moiety (figure) which facilitates transport to the periplasm are being developed which show promise against Gram-negative organisms including Acinetobacter spp.

Methods

YU253911, an example of this new class of antibacterials, was characterized in vitro. Minimum inhibitory concentrations (MICs) were determined by broth microdilution against a collection of 200 previously described (whole-genome sequencing) Acinetobacter isolates including 98 carbapenem-resistant A. baumannii strains. YU253911’s antimicrobial activity was also evaluated in combination with complementary PBP agents and β-lactamase inhibitors by MIC and disc diffusion testing. All studies were performed according to current Clinical and Laboratory Standards Institute (CLSI) guidelines using iron-depleted media. Breakpoints for ceftazidime were arbitrarily chosen as reference.

Results

Using ceftazidime (breakpoint ≤8 μg/mL) as a comparator, 175 of the 200 Acinetobacter isolates were susceptible to YU253911, which possessed an MIC50 of 0.5 μg/mL and an MIC90 of 16 μg/mL. This compared favorably to all previously tested β-lactams including penicillins, cephalosporins, monobactams and carbapenems (MIC50s 2 to >16 μg/mL). Against the subset of carbapenem-resistant A. baumannii isolates, YU253911’s potency was similar with an MIC50 of 1 μg/mL. Genetic analysis showed β-lactamase genes, including OXA-23 and other carbapenemases, were common in both YU253911-resistant and susceptible strains.

Conclusion

YU253911 demonstrates promising in vitro potency against a collection of Acinetobacter isolates and compares favorably to β-lactam antibiotics. Understanding interactions with PBP agents and β lactamase inhibitors is being explored as well as further studies on the mechanism of resistance.

Disclosures

All authors: No reported disclosures.
688. In Vitro Activity of Eravacycline, a New Tetracycline Analog, and Comparators Against the Six Most Commonly Isolated Ribotypes of Clostridioides difficile
Authors: Basseres Eugenie , Miranda Julie , Gonzales-Luna Anne J , Carlson Travis J , Rashid Tasnuva , Alam M Jahangir , Garey Kevin W
Published: October 2019

Background

Eravacycline is a novel, tetracycline class antibacterial indicated for the treatment of complicated intra-abdominal infections in adults. In clinical trials, patients given eravacycline had a low likelihood of developing Clostridioides difficile infection (CDI). We hypothesized this was likely due, in part, to the in vitro susceptibility of eravacycline to C. difficile. The purpose of this study was to test the in vitro susceptibility of eravacycline vs. comparators on contemporary clinical isolates representing common ribotypes, including isolates with decreased susceptibility to metronidazole and vancomycin.

Methods

Two hundred and thirty-four isolates from our biobank were selected from the six most common ribotypes (F001, F002, F014-020, F027, F106, and F255). Minimum inhibitory concentrations (MIC) at 24 hours were measured according to CLSI guidelines for eravacycline, vancomycin, metronidazole and fidaxomicin. MICs results were tabulated and are presented as the geometric mean by ribotype.

Results

Geometric MIC results are shown in Table 1. Eravacycline was the most potent antimicrobial tested followed by fidaxomicin, metronidazole, and vancomycin. Results were consistent amongst all ribotypes, including isolates with reduced susceptibility to vancomycin and metronidazole.

Conclusion

Eravacycline displayed potent in vitro activity against a large collection of clinical C. difficile isolates. These data provide insight into why patients given eravacycline had a low likelihood of developing CDI and support further research to better understand the use of eravacycline to prevent or potentially treat patients with CDI.

Disclosures

All authors: No reported disclosures.
694. In vitro Antibacterial Activity of Sulbactam–Durlobactam (ETX2514SUL) Against 121 Recent Acinetobacter baumannii Isolated from Patients in India
Authors: Miller Alita , McLeod Sarah , Mathur Tarun , Morrissey Ian
Published: October 2019

Background

The incidence of infections caused by multidrug-resistant Acinetobacter baumannii is increasing at an alarming rate in Southeast Asia and other parts of the world. Sulbactam (SUL) has intrinsic antibacterial activity against A. baumannii; however, the prevalence of β-lactamases in this species has limited its therapeutic use. Durlobactam (ETX2514, DUR) is a novel β-lactamase inhibitor with broad-spectrum activity against Ambler class A, C and D β-lactamases. DUR restores SUL in vitro activity against multidrug-resistant A. baumannii. Against >3,600 globally diverse, clinical isolates from 2012–2017, addition of 4 mg/L DUR reduced the SUL MIC90 from >32 to 2 mg/L. SUL-DUR is currently in Phase 3 clinical development for the treatment of infections caused by carbapenem-resistant Acinetobacter spp.The goal of this study was to determine the activity of SUL-DUR and comparator antibiotics (amikacin (AMK), ampicillin-sulbactam (AMP-SUL), cefoperazone-sulbactam (CFP-SUL) and meropenem (MEM)) against A. baumannii isolated from hospitalized patients in India.

Methods

A total of 121 clinical A. baumannii isolates from multiple hospital settings and infection sources were collected between 2016–2019 from six geographically diverse hospitals in India. Species identification was performed by MALDI-TOF. Susceptibility of these isolates to SUL-DUR (10µg/10µg) and comparator antibiotics was determined by disk diffusion using CLSI methodology and interpretive criteria, except for CFP-SUL, for which resistance was defined using breakpoints from the CFP-SUL package insert.

Results

As shown in Table 1, resistance of this collection of isolates to marketed agents was extremely high. In contrast, based on preliminary breakpoint criteria, only 11.5% of isolates were resistant to SUL-DUR.

Conclusion

The in vitro antibacterial activity of SUL-DUR was significantly more potent than comparator agents against multidrug-resistant A. baumannii isolates collected from diverse sites in India. These data support the continued development of SUL-DUR for the treatment of antibiotic-resistant infections caused by A. baumannii.

Disclosures

All authors: No reported disclosures.
705. Pharmacokinetics (PK) and Safety of Lefamulin (LEF) After Single Intravenous Dose Administration in Subjects With Impaired Renal Function and in Those Requiring Hemodialysis
Authors: Wicha Wolfgang , Marbury Thomas C , Dowell James A , Lykens Lori , Leister Cathie , Ermer James , Gelone Steven P
Published: October 2019

Background

Renal comorbidities are common in patients hospitalized with community-acquired bacterial pneumonia (CABP). LEF, a novel pleuromutilin antibiotic (IV/oral), was generally well tolerated and noninferior to moxifloxacin in two phase 3 studies of adults with CABP. We investigated the PK and safety of LEF and its main metabolite, BC-8041, in subjects with severe renal impairment and those requiring hemodialysis (HD).

Methods

In this open-label study, subjects were allocated to 1 of 3 groups based on renal function level. Severe subjects (estimated glomerular filtration rate <30 mL/minute/1.73 m2, not on HD, Severe) were matched (gender, age, and weight) to subjects with normal renal function (estimated creatinine clearance ≥90 mL/minute, Normal). Subjects in the Normal and Severe groups received a single 1-hour 150 mg LEF infusion. Subjects in the HD group started HD within 1 hour after LEF infusion (“On-dialysis”) and on a nondialysis day (“Off-dialysis”). Blood and urine samples were collected predose and over a 36-hour period postdose for PK analysis; LEF and BC-8041 were assayed in plasma and urine with validated methods. Safety assessments included treatment-emergent adverse events (TEAEs), labs, vital signs, and electrocardiograms.

Results

23 subjects enrolled in and completed the study (n = 7, Normal; n = 8, Severe; n = 8, HD). LEF and BC-8041 pharmacokinetic parameters (table) were comparable between the Normal and Severe groups and between the On-dialysis and Off-dialysis treatment periods for the HD group. The majority of LEF and BC-8041 were excreted nonrenally in Normal and Severe subjects and were not measurably filtered into dialysate. TEAEs were reported in 2 (28.6%) subjects in the Normal group, 4 (50%) in the Severe group, and 4 (50%) in the HD group. None of the TEAEs were serious or led to study drug discontinuation. Within 4 h post-dose, the maximum mean change from baseline in the QTcF interval was 8.9, 6.6, 15.9, and 17.6 msec in the normal, severe, on-dialysis, and off-dialysis groups, respectively.

Conclusion

No dosage adjustment is required for LEF when treating subjects with severe renal impairment, and LEF can be administered without regard to HD timing. LEF was generally well tolerated in all subjects regardless of renal function status.

Disclosures

All authors: No reported disclosures.
706. In Vitro Activity of Ceftazidime–Avibactam and Comparator Agents Against MDR Enterobacteriaceae and Pseudomonas aeruginosa Collected in Latin America During the ATLAS Global Surveillance Program 2016–2017
Authors: Lob Sibylle , Kazmierczak Krystyna , Stone Gregory , Sahm Daniel F
Published: October 2019

Background

Ceftazidime–avibactam (CAZ-AVI) is a β-lactam/non-β-lactam β-lactamase inhibitor combination that can inhibit class A, C and some class D β-lactamases. Resistance caused by these β-lactamases often results in multidrug-resistance (MDR). This study evaluated the in vitro activity of CAZ-AVI and comparators against MDR Enterobacteriaceae and Pseudomonas aeruginosa isolates collected from patients in Latin America.

Methods

Nonduplicate clinical isolates were collected in 2016–2017 in 6 countries in Latin America. Susceptibility testing was performed using CLSI broth microdilution and interpreted using CLSI 2019 and FDA (tigecycline) breakpoints. MDR was defined as nonsusceptible (NS) (intermediate or resistant) to ≥3 of 7 sentinel drugs: amikacin, aztreonam, cefepime, levofloxacin, colistin, meropenem, and piperacillin–tazobactam.

Results

The activity of CAZ-AVI and comparators against all isolates and MDR subsets is shown in the table. MDR rates ranged from 28.4% among E. cloacae to 41.5% among K. pneumoniae. CAZ-AVI was active against >97% of Enterobacteriaceae isolates and maintained activity against >92% of MDR isolates of the examined species. No other tested drug consistently exceeded this activity. Among P. aeruginosa, CAZ-AVI was active against 87% of all isolates and 63% of MDR isolates; only colistin was more active. The two most common MDR phenotypes among Enterobacteriaceae were (1) NS to aztreonam, cefepime, and levofloxacin (n = 580, 41% of all MDR Enterobacteriaceae; 100% susceptible to CAZ-AVI) and (2) NS to aztreonam, cefepime, levofloxacin, and piperacillin–tazobactam (n = 301, 21% of all MDR isolates; 99.7% susceptible to CAZ-AVI). The two most common MDR phenotypes among P. aeruginosa were (1) NS to all sentinel drugs except colistin (n = 154, 33% of all MDR isolates; 30.5% susceptible to CAZ-AVI) and (2) NS to all drugs except colistin and amikacin (n = 97, 21% of all MDR isolates; 70.1% susceptible to CAZ-AVI).

Conclusion

These in vitro data suggest that CAZ-AVI can be an effective treatment option for infections caused by MDR Enterobacteriaceae and P. aeruginosa collected in Latin America.

Disclosures

All authors: No reported disclosures.