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Background Staphylococcus aureus is a common cause of biofilm-mediated left ventricular device (LVAD) infections which are difficult to resolve with antibiotics alone and are associated with substantial morbidity and mortality. Recently, bacteriophages (phage) therapy has been used to resolve LVAD infections in a few cases. Our goal was to assess in vitro susceptibility and anti-biofilm activity of two S. aureus bacteriophages against clinical isolates from patients with S. aureus LVAD infections in order to develop a S. aureus phage cocktail for clinical use. Methods Two bacteriophages, OMS1 and OMS2, from the Israeli Phage Bank, were assessed for lytic activity against 15 S.aureus isolates (9 methicillin resistant, MRSA and 6 methicillin susceptible, MSSA) via agar overlay method and plaque forming units (PFU)/mL were enumerated. We then formed bacterial biofilms after overnight incubation at 120 rpm in a 96-well plates in duplicate; experiments were repeated thrice. Wells were then treated with tryptic soy broth (TSB, control) or TSB containing phage at 109 PFU/mL for 24 hours. After washing, biofilms were stained with crystal violet and biomass quantified via optical density at 570mm. Results All bacterial isolates were susceptible to both phages via agar overlay to varying degrees as determined by phage titers obtained via serial dilutions (Figure 1a, 1b). OMS1 led to significant reduction in biofilm of 7/9 MRSA and 3/6 MSSA isolates and OMS2 reduced biofilms in 9/9 MRSA and 4/6 MSSA isolates (Figure 1c). Phage titers and Biofilm Biomass Figure 1a) Phage titers in PFU/ml obtained from each bacterial isolate via agar overlay method. 1b) Representative agar plate demonstrating lytic plaques from OMS1 and OMS2 on a Staphylococcus aureus LVAD isolate. 1c) Biofilm biomass of Staphylococcus aureus isolates alone (SA) or with individual phage (SA+OMSA1 and SA=OMS2) assessed by optical density readings at 570 nm; error bars represent standard error of the mean. Conclusion We demonstrated in vitro lytic and anti-biofilm activity of 2 S. aureus phages against clinical S. aureus isolates from patients with LVAD infection. Our data suggests that phage susceptibility measured with agar overlay does not always correlate with phage susceptibility of S. aureus biofilms, suggesting that more than one method should be used to assess in vitro activity. We plan to assess for synergistic activity with the phage combination. Disclosures Ryan K. Shields, PharmD, MS, Shionogi (Consultant, Research Grant or Support) Ran Nir-Paz, MD, BiomX (Consultant)Technophage (Scientific Research Study Investigator, Advisor or Review Panel member) Saima Aslam, MD, MS, BioMx (Consultant)Cystic Fibrosis Foundation (Grant/Research Support)Gilead (Consultant)Johnson and Johnson (Consultant)Merck (Consultant)

Background The effect of time from stroke onset to thrombectomy in the extended time window remains poorly characterized. Aim We aimed to analyze the relationship between time to treatment and clinical outcomes in the early versus extended time windows. Methods Proximal anterior circulation occlusion patients from a multicentric prospective registry were categorized into early (≤6 h) or extended (>6–24 h) treatment window. Patients with baseline National Institutes of Health Stroke Scale (NIHSS) ≥ 10 and intracranial internal carotid artery or middle cerebral artery-M1-segment occlusion and pre-morbid modified Rankin scale (mRS) 0–1 (“DAWN-like” cohort) served as the population for the primary analysis. The relationship between time to treatment and 90-day mRS, analyzed in ordinal (mRS shift) and dichotomized (good outcome, mRS 0–2) fashion, was compared within and across the extended and early windows. Results A total of 1603 out of 2008 patients qualified. Despite longer time to treatment (9[7–13.9] vs. 3.4[2.5–4.3] h, p Conclusions The impact of time to thrombectomy on outcomes appears to be time dependent with a steep influence in the early followed by a less significant plateau in the extended window. However, every effort should be made to shorten treatment times regardless of ischemia duration.

Background and Purpose: Advanced imaging has been increasingly used for patient selection in endovascular stroke therapy. The impact of imaging selection modality on endovascular stroke therapy clinical outcomes in extended time window remains to be defined. We aimed to study this relationship and compare it to that noted in early-treated patients. Methods: Patients from a prospective multicentric registry (n=2008) with occlusions involving the intracranial internal carotid or the M1- or M2-segments of the middle cerebral arteries, premorbid modified Rankin Scale score 0 to 2 and time to treatment 0 to 24 hours were categorized according to treatment times within the early (0–6 hour) or extended (6–24 hour) window as well as imaging modality with noncontrast computed tomography (NCCT)±CT angiography (CTA) or NCCT±CTA and CT perfusion (CTP). The association between imaging modality and 90-day modified Rankin Scale, analyzed in ordinal (modified Rankin Scale shift) and dichotomized (functional independence, modified Rankin Scale score 0–2) manner, was evaluated and compared within and across the extended and early windows. Results: In the early window, 332 patients were selected with NCCT±CTA alone while 373 also underwent CTP. After adjusting for identifiable confounders, there were no significant differences in terms of 90-day functional disability (ordinal shift: adjusted odd ratio [aOR], 0.936 [95% CI, 0.709–1.238], P =0.644) or independence (aOR, 1.178 [95% CI, 0.833–1.666], P =0.355) across the CTP and NCCT±CTA groups. In the extended window, 67 patients were selected with NCCT±CTA alone while 180 also underwent CTP. No significant differences in 90-day functional disability (aOR, 0.983 [95% CI, 0.81–1.662], P =0.949) or independence (aOR, 0.640 [95% CI, 0.318–1.289], P =0.212) were seen across the CTP and NCCT±CTA groups. There was no interaction between the treatment time window (0–6 versus 6–24 hours) and CT selection modality (CTP versus NCCT±CTA) in terms of functional disability at 90 days ( P =0.45). Conclusions: CTP acquisition was not associated with better outcomes in patients treated in the early or extended time windows. While confirmatory data is needed, our data suggests that extended window endovascular stroke therapy may remain beneficial even in the absence of advanced imaging.

BackgroundAntibiotics are among the most frequently administered drugs globally, yet they are often prescribed inappropriately. Guidelines for prescribing are developed by expert committees at international and national levels to form regional standards and by local experts to form hospital guidance documents. Our aim was to assess variability in antibiotic prescription guidelines for both regional standards and individual hospitals.MethodsA search through 3 publicly accessible databases from February to June 2018 led to a corpus of English language guidance documents from 70 hospitals in 12 countries and regional standards from 7 academic societies.ResultsGuidelines varied markedly in content and structure, reflecting a paucity of rules governing their format. We compared recommendations for 3 common bacterial infections: community-acquired pneumonia, urinary tract infection, and cellulitis. Hospital guidance documents and regional standards frequently disagreed on preferable antibiotic classes for common infections. Where agreement was observed, guidance documents appeared to inherit recommendations from their respective regional standards. Several regional prescribing patterns were identified, including a greater reliance on penicillins over cephalosporins in the United Kingdom and fluoroquinolones in the United States. Regional prescribing patterns could not be explained by antibiotic resistance or costs. Additionally, literature that cited underlying recommendations did not support the magnitude of recommendation differences observed.ConclusionsThe observed discordance among prescription recommendations highlights a lack of evidence for superior treatments, likely resulting from a preponderance of noninferiority trials comparing antibiotics. In response, we make several suggestions for developing guidelines that support best practices of antibiotic stewardship.

Carbapenem-nonsusceptible Citrobacter spp. (CNSC) are increasingly recognized as health care-associated pathogens. Information regarding their clinical epidemiology, genetic diversity, and mechanisms of carbapenem resistance is lacking. We examined microbiology records of adult patients at the University of Pittsburgh Medical Center (UMPC) Presbyterian Hospital (PUH) from 2000 to 2018 for CNSC, as defined by ertapenem nonsusceptibility. Over this time frame, the proportion of CNSC increased from 4% to 10% (P = 0., Carbapenem-nonsusceptible Citrobacter spp. (CNSC) are increasingly recognized as health care-associated pathogens. Information regarding their clinical epidemiology, genetic diversity, and mechanisms of carbapenem resistance is lacking. We examined microbiology records of adult patients at the University of Pittsburgh Medical Center (UMPC) Presbyterian Hospital (PUH) from 2000 to 2018 for CNSC, as defined by ertapenem nonsusceptibility. Over this time frame, the proportion of CNSC increased from 4% to 10% (P = 0.03), as did daily defined carbapenem doses/1,000 patient days (6.52 to 34.5; R2 = 0.831; P

Ceftazidime-avibactam and cefiderocol are two of the latest generation β-lactam agents that possess expanded activity against highly drug-resistant bacteria, including carbapenem-resistant Enterobacterales Here, we show that structural changes in AmpC β-lactamases can confer reduced susceptibility to both agents. A multidrug-resistant Enterobacter cloacae clinical strain (Ent385) was found to be resistant to ceftazidime-avibactam and cefiderocol without prior exposure to either agent. The AmpC β-lactamase of Ent385 (AmpCEnt385) contained an alanine-proline deletion at positions 294 and 295 (A294_P295del) in the R2 loop. AmpCEnt385 conferred reduced susceptibility to ceftazidime-avibactam and cefiderocol when cloned into Escherichia coli TOP10. Purified AmpCEnt385 showed increased hydrolysis of ceftazidime and cefiderocol compared to AmpCEnt385Rev, in which the deletion was reverted. Comparisons of crystal structures of AmpCEnt385 and AmpCP99, the canonical AmpC of E. cloacae complex, revealed that the two-residue deletion in AmpCEnt385 induced drastic structural changes of the H-9 and H-10 helices and the R2 loop, which accounted for the increased hydrolysis of ceftazidime and cefiderocol. The potential for a single mutation in ampC to confer reduced susceptibility to both ceftazidime-avibactam and cefiderocol requires close monitoring.

Cefiderocol is a newly approved siderophore cephalosporin that demonstrates expanded in vitro activity against multidrug-resistant Gram-negative bacteria. In two challenging cases reported here, cefiderocol shows potential utility as salvage therapy against difficult-to-treat pathogens with limited or no treatment options; however, two multicenter, randomized clinical trials have yielded mixed results among cefiderocol-treated patients. Taken together, clinicians must balance a clear need for cefiderocol in clinical practice with the uncertainties that have stemmed from the available data.

Carbapenem-non-susceptible Citrobacter spp. (CNSC) are increasingly recognized as healthcare-associated pathogens. Information regarding their clinical epidemiology, genetic diversity, and mechanisms of carbapenem resistance is lacking. We examined microbiology records of adult patients at the University of Pittsburgh Medical Center (UMPC) Presbyterian Hospital (PUH) from 2000-2018 for CNSC, as defined by ertapenem non-susceptibility. Over this timeframe, the proportion of CNSC increased from 4% to 10% (P=0.03), as did carbapenem daily defined doses/1000 patient days (6.52 to 34.5, R2=0.831, P2=0.660). Twenty CNSC isolates from 19 patients at PUH and other UPMC hospitals were available for further analysis, including whole-genome short-read sequencing and additional antimicrobial susceptibility testing. Of the 19 patients, nearly all acquired CNSC in the healthcare setting and over half had polymicrobial cultures containing at least one other organism. Among the 20 CNSC isolates, C. freundii was the predominant species identified (60%). CNSC genomes were compared with genomes of carbapenem-susceptible Citrobacter spp. from UPMC, and with other publicly available CNSC genomes. Isolates encoding carbapenemases (blaKPC-2, blaKPC-3, and blaNDM-1) were also long-read sequenced, and their carbapenemase-encoding plasmid sequences were compared with one another and with publicly available sequences. Phylogenetic analysis of 102 UPMC Citrobacter spp. genomes showed that CNSC from our setting did not cluster together. Similarly, a global phylogeny of 64 CNSC genomes showed a diverse population structure. Our findings suggest that both local and global CNSC populations are genetically diverse, and that CNSC harbor carbapenemase-encoding plasmids found in other Enterobacterales.

Ceftazidime-avibactam and cefiderocol are two of the latest generation β-lactam agents that possess expanded activity against highly drug-resistant bacteria, including carbapenem-resistant Enterobacterales. Here, we show that structural changes in AmpC β-lactamases can confer reduced susceptibility to both agents. A multidrug-resistant Enterobacter cloacae clinical strain (Ent385) was found to be resistant to ceftazidime-avibactam and cefiderocol without prior exposure to either agent. The AmpC β-lactamase of Ent385 (AmpC(Ent385)) contained an alanine-proline deletion at positions 294 and 295 (A294_P295del) in the R2 loop. AmpC(Ent385) conferred reduced susceptibility to ceftazidime-avibactam and cefiderocol when cloned into Escherichia coli TOP10. Purified AmpC(Ent385) showed increased hydrolysis of ceftazidime and cefiderocol compared to AmpC(Ent385Rev), in which the deletion was reverted. Comparisons of crystal structures of AmpC(Ent385) and AmpC(P99), the canonical AmpC of E. cloacae complex, revealed that the two-residue deletion in AmpC(Ent385) induced drastic structural changes of the H-9 and H-10 helices and the R2 loop, which accounted for the increased hydrolysis of ceftazidime and cefiderocol. The potential for a single mutation in ampC to confer reduced susceptibility to both ceftazidime-avibactam and cefiderocol requires close monitoring.

Isavuconazole (ISA) is a triazole antifungal with activity against yeasts and molds. We established a population pharmacokinetic (pop PK) model of intravenous (i.v.) ISA to identify covariates that affect pharmacokinetics, using plasma samples from solid-organ transplant (SOT) recipients receiving peritransplant prophylaxis. Samples (n = 471) from 79 SOT recipients were utilized for pop PK analysis using nonlinear mixed-effect modeling NONMEM software. ISA (i.v.) PK parameters were best described by a two-compartment model. Significant covariates were sex on clearance (∼53% higher in women than men) and body mass index on peripheral volume of distribution. Incorporating drug exposure into Monte Carlo simulations, we demonstrated that standard ISA dosing is likely to attain the PK-pharmacodynamic (PD) target (area under the concentration curve/MIC ratio [AUC/MIC]) for treatment effectiveness against almost all infections caused by Aspergillus fumigatus isolates exhibiting MICs of ≤0.5 μg/ml (modal MIC). In contrast, standard dosing is predicted to attain PK-PD targets against

Background In Pseudomonas aeruginosa, fluoroquinolone exposure promotes resistance to carbapenems through upregulation of efflux pumps and transcriptional downregulation of the porin OprD. Evidence of this effect among hematologic malignancy (HM) patients or hematopoietic cell transplant (HCT) recipients receiving fluoroquinolone prophylaxis for neutropenia is lacking. Methods We retrospectively evaluated episodes of P. aeruginosa bloodstream infections in HM patients or HCT recipients over a 7-year period at our institution. We determined the association of fluoroquinolone prophylaxis at the time of infection with meropenem susceptibility of P. aeruginosa breakthrough isolates and risk factors for meropenem nonsusceptibility. Whole-genome sequencing (WGS) and phenotypic assessments of meropenem efflux pump activity were performed on select isolates to determine the mechanisms of meropenem resistance. Results We analyzed 55 episodes of P. aeruginosa bacteremia among 51 patients. Breakthrough bacteremia while on fluoroquinolone prophylaxis was associated with nonsusceptibility to meropenem, but not to antipseudomonal β-lactams or aminoglycosides. The receipt of fluoroquinolone prophylaxis was independently predictive of bacteremia with a meropenem-nonsusceptible isolate. All meropenem-nonsusceptible isolates analyzed by WGS contained oprD inactivating mutations, and all meropenem-nonsusceptible isolates tested demonstrated reductions in the meropenem minimum inhibitory concentration in the presence of an efflux pump inhibitor. A phylogenetic analysis based on WGS revealed several clusters of closely related isolates from different patients. Conclusions Fluoroquinolone prophylaxis in HM patients and HCT recipients is associated with breakthrough bacteremia with meropenem-nonsusceptible P. aeruginosa strains, likely due to both mutations increasing efflux pump activity and the epidemiology of P. aeruginosa bloodstream infections in our patient population.

BACKGROUND The effect of endovascular thrombectomy that is performed more than 6 hours after the onset of ischemic stroke is uncertain. Patients with a clinical deficit that is disproportionately severe relative to the infarct volume may benefit from late thrombectomy. METHODS We enrolled patients with occlusion of the intracranial internal carotid artery or proximal middle cerebral artery who had last been known to be well 6 to 24 hours earlier and who had a mismatch between the severity of the clinical deficit and the infarct volume, with mismatch criteria defined according to age (= 80 years). Patients were randomly assigned to thrombectomy plus standard care (the thrombectomy group) or to standard care alone (the control group). The coprimary end points were the mean score for disability on the utility-weighted modified Rankin scale (which ranges from 0 [death] to 10 [no symptoms or disability]) and the rate of functional independence (a score of 0, 1, or 2 on the modified Rankin scale, which ranges from 0 to 6, with higher scores indicating more severe disability) at 90 days. RESULTS A total of 206 patients were enrolled; 107 were assigned to the thrombectomy group and 99 to the control group. At 31 months, enrollment in the trial was stopped because of the results of a prespecified interim analysis. The mean score on the utility-weighted modified Rankin scale at 90 days was 5.5 in the thrombectomy group as compared with 3.4 in the control group (adjusted difference [Bayesian analysis], 2.0 points; 95% credible interval, 1.1 to 3.0; posterior probability of superiority, >0.999), and the rate of functional independence at 90 days was 49% in the thrombectomy group as compared with 13% in the control group (adjusted difference, 33 percentage points; 95% credible interval, 24 to 44; posterior probability of superiority, >0.999). The rate of symptomatic intracranial hemorrhage did not differ significantly between the two groups (6% in the thrombectomy group and 3% in the control group, P = 0.50), nor did 90-day mortality (19% and 18%, respectively; P = 1.00). CONCLUSIONS Among patients with acute stroke who had last been known to be well 6 to 24 hours earlier and who had a mismatch between clinical deficit and infarct, outcomes for disability at 90 days were better with thrombectomy plus standard care than with standard care alone. (Funded by Stryker Neurovascular; DAWN ClinicalTrials.gov number, NCT02142283.)

Background Rescue ECMO has been used worldwide in patients (pts) with ARDS caused by COVID-19. Bacterial super-infections affect 3.5-14.3% of hospitalized pts with COVID-19. Pts requiring ECMO may be at an increased risk of infection due to their severity of illness, gut translocation and ECMO impact on host immunity. Methods This was a retrospective review of pts requiring ECMO for COVID-19 from April 2020-2021 at a single center. Strict definitions of infections (including ventilator-associated PNA, VAP) were in accordance with CDC criteria. Results 43 ECMO pts with 1065 ECMO days were evaluated. Median age was 53 yrs (range: 21-62) and median BMI was 36.2 (range: 19.4-75.8). 70% were men and 65% were white. 37 patients (86%) experienced a total of 40 infectious episodes with a median onset from ECMO cannulation to first infection of 10.5d (range: 4-50). Median SOFA and SAPSII scores at time of infection were 12 (6-20) and 63 (30-90), respectively. PNA was the most common infection (78%, with 19% of cases complicated by bacteremia and 3% by empyema) (Fig. 1). The most common organisms isolated were Enterobacterales (37%), S. aureus (25%) and P. aeruginosa (16%) (Fig. 2). Only 2% of all organisms were multi-drug resistant. 3 pts had fungal infections (1 candidemia, 2 aspergillus PNA). Duration of ECMO was significantly longer for infected pts (26d, range: 5-92d) vs (11d, range: 3-24d), p=.01. 95% of infected pts had received steroids vs. 67% of uninfected pts, p=0.09. Treatment success at 1 week was 50%, and 24% and 40% of pts had recurrent infections and persistent/recurrent organisms in clinical cultures, respectively. S. aureus (54%) and Enterobacterales (26%) were associated with persistent or recurrent clinical cultures, requiring prolonged antimicrobial therapy. Mortality rate at 30 days was 65% and was significantly higher for pts with infection than those without (67% vs 33%, p=.02). Conclusion Super-infection (most commonly PNA) occurred in almost all COVID-19 pts requiring ECMO for >4 days, and was a significant risk factor for death. Recurrent infections among survivors were common, especially when caused by Enterbacterales or S. aureus. Super-infection and mortality rates of ARDS pts on ECMO for COVID-19 were worse than for ARDS pts on ECMO for influenza at our center. Disclosures Ryan K. Shields, PharmD, MS, Shionogi (Consultant, Research Grant or Support) Fernanda P. Silveira, MD, MS, FIDSA, Ansun (Individual(s) Involved: Self): Grant/Research Support; Novartis (Individual(s) Involved: Self): Grant/Research Support; Qiagen (Individual(s) Involved: Self): Grant/Research Support; Shire (Individual(s) Involved: Self): Advisor or Review Panel member, Grant/Research Support; SlieaGen (Individual(s) Involved: Self): Grant/Research Support; Whiscon (Individual(s) Involved: Self): Grant/Research Support Cornelius J. Clancy, MD, Merck (Grant/Research Support)

Rationale Efficacy of mechanical thrombectomy for acute stroke due to large vessel occlusion initiated beyond 6 h of time last seen well has not been demonstrated in randomized trials. Aim To establish whether subjects considered to have substantial areas of salvageable brain based on age-adjusted clinical core mismatch who can undergo endovascular treatment within 6–24 h from time last seen well (TLSW) have better outcomes at three months compared to subjects treated with standard medical therapy alone. Age-adjusted clinical core mismatch is defined by age (≤80 or >80 years), baseline National Institutes of Health Stroke Scale (NIHSS) (10–20 or ≥21), and core size (0–20 cm3 in subjects older than 80 and, in subjects younger than 80, 0–30 cm3 with NIHSS 10–20 and 31–50 cm3 with NIHSS ≥21). Design Prospective, randomized, multicenter, Bayesian adaptive-enrichment, open label trial with blinded endpoint assessment. For the purpose of enrolment, ischemic core size will be evaluated by CT perfusion or magnetic resonance imaging-diffusion-weighted imaging measured by automated software (RAPID). Procedures Subjects with acute ischemic stroke due to computed tomography angiography- or magnetic resonance angiogram-proven arterial occlusion of the intracranial internal carotid and/or proximal middle cerebral artery (M1) with age-adjusted clinical core mismatch in whom treatment can be initiated between 6 and 24 h from TSLW are randomized in a 1:1 ratio to receive mechanical embolectomy with the Trevo device or medical management alone. Sequential interim analyses allowing adaptation of enrolment criteria or stopping new enrolment for futility or predicted success will occur in every 50 randomized patients starting at 150 to a maximum of 500 patients. Study outcomes The primary endpoint is the modified Rankin Scale score at 90 days. The primary safety outcome is stroke-related mortality at 90 days. Analysis The primary endpoint, expressed as a utility-weighted modified Rankin Scale score is analyzed using a Bayesian posterior probability with adjustment for ischemic core size. For regulatory reasons, a nested co-primary endpoint analysis was added consisting of the proportion of subjects with modified Rankin Scale 0–2 between the active and control groups also analyzed using a Bayesian model.

Background There is marked interest in using DNA-based methods to detect antimicrobial resistance (AMR), with targeted polymerase chain reaction (PCR) approaches increasingly being incorporated into clinical care. Whole-genome sequencing (WGS) could offer significant advantages over targeted PCR for AMR detection, particularly for species where mutations are major drivers of AMR. Methods Illumina MiSeq WGS and broth microdilution (BMD) assays were performed on 90 bloodstream isolates of the 4 most common gram-negative bacteria causing bloodstream infections in neutropenic patients. The WGS data, including both gene presence/absence and detection of mutations in an array of AMR-relevant genes, were used to predict resistance to 4 β-lactams commonly used in the empiric treatment of neutropenic fever. The genotypic predictions were then compared to phenotypic resistance as determined by BMD and by commercial methods during routine patient care. Results Of 133 putative instances of resistance to the β-lactams of interest identified by WGS, only 87 (65%) would have been detected by a typical PCR-based approach. The sensitivity, specificity, and positive and negative predictive values for WGS in predicting AMR were 0.87, 0.98, 0.97, and 0.91, respectively. Using BMD as the gold standard, our genotypic resistance prediction approach had a significantly higher positive predictive value compared to minimum inhibitory concentrations generated by commercial methods (0.97 vs 0.92; P = .025). Conclusions These data demonstrate the potential feasibility of using WGS to guide antibiotic treatment decisions for patients with life-threatening infections for an array of medically important pathogens.

Background Tedizolid (TZD) is approved for acute bacterial skin and skin structure infections (ABSSSI), but often used for complicated infections to avoid linezolid (LZD) adverse events (AE), particularly when long-term treatment is indicated. This studied aimed to characterize the tolerability of TZD, including patients (pts) receiving prolonged treatment. Methods Retrospective review of pts who received TZD > 72 hours. Thrombocytopenia was defined as a 50% decrease from baseline platelet count. Favorable clinical outcome was defined as completing therapy without an AE or hospital readmission within 30 days. Results 86 pts accounting for 102 courses were included. Median age of pts was 57 years and 43% were immunocompromised. Median duration of TZD therapy was 8 days (range: 4 – 350) and 32% of courses were >14 days. Common indications were ABSSSI (n=42), bacteremia (n=15), intra-abdominal infection (n=11), and pneumonia (n=10). 47% and 5% of courses were associated with MRSA or VRE and M. abscessus, respectively. 44% of TZD courses were preceded by treatment failure or AE associated with alternative therapies. AEs attributed to LZD were documented in 13 patients: thrombocytopenia (n=11), lactic acidosis (n=1), or both (n=1). Serotonergic agents were administered during 76% of TZD courses; however, no patient developed serotonin syndrome. 8% of TZD courses were stopped prematurely due to AEs that included thrombocytopenia (n=3), gastrointestinal intolerance (n=2), confusion (n=1), eosinophilia (n=1) and thrombocytopenia with lactic acidosis (n=1). All cases of thrombocytopenia occurred in pts with baseline platelets < 100,000 cells/L. 79% of pts receiving > 14 days of TZD completed therapy successfully without AEs. Among pts who failed alternative therapies, 74% were able to tolerate TZD and completed therapy. Overall, 80% of courses were completed with a favorable outcome. Clinical Outcomes of Extended TZD Therapy Conclusion The safety of prolonged TZD treatment is not well-described. In our experience, TZD was well-tolerated, including among pts who failed alternative therapy. No pt receiving concomitant serotonergic agents developed serotonin syndrome and thrombocytopenia occurred exclusively among pts with low baseline platelets. Treatment courses >14 days were not associated with an increase in the rate of AEs. Disclosures Rachel V. Marini, PharmD, Merck (Research Grant or Support) Ryan K. Shields, PharmD, MS, Allergan (Advisor or Review Panel member, Research Grant or Support)Entasis (Advisor or Review Panel member)Melinta (Research Grant or Support)Menarini (Consultant)Merck (Advisor or Review Panel member, Research Grant or Support)Shionogi (Advisor or Review Panel member, Research Grant or Support)Summit (Advisor or Review Panel member)Tetraphase (Research Grant or Support)Venatorx (Advisor or Review Panel member, Research Grant or Support)

Background Ceftazidime-avibactam (CAZ-AVI) is used to treat multidrug-resistant infections. There are limited pharmacokinetic (PK) data among critically-ill patients (pts) and no dosing recommendations for those receiving continuous renal replacement therapy (CRRT). Methods We conducted a PK study of CAZ-AVI among pts with and without CRRT. Serial blood samples were collected at 0 (pre-dose), 2, 4, 6, and 8 hours after CAZ-AVI administration. All doses were infused over 2h. Samples were centrifuged and plasma stored at -80°C until analysis by a Shimadzu Nexera XD UHPLC with a Shimadzu 8045 MS. Transitions were monitored in positive mode for CAZ (m/z 274.05 < 80.05) and negative mode for AVI (264.00 < 95.90). The assay was reproducible and linear over a range of 0.1 – 20 µg/mL for AVI and 1 – 200 µg/mL for CAZ. non-compartmental analyses were used. Results 96 plasma samples from 20 pts were included in the study. Median age was 56 years (range: 31 – 74), 55% were male, and 90% were in the ICU at the time of collection. CZA dosing regimens included 2.5g IV q 8h (n=15), 1.25g IV q 8h (n=2), 0.94g IV q 24h (n=1), and 0.94g IV q 48h (n=2). 7 pts received CRRT (median blood and dialysate flow rates were 250 mL/min and 2.5 L/h, respectively; 86% received 2.5g IV q 8h) and 2 pts received intermittent hemodialysis (iHD). Among remaining pts, median creatinine clearance (CrCl) by Cockcroft-Gault was 91ml/min (range: 37 – 168 ml/min). PK values for CAZ and AVI are shown in the Table. Individual concentration-time profiles for patients receiving 2.5g IV q 8h are shown in the Figure. For patients receiving 2.5g IV q8h, CAZ and AVI median (IQR) AUCs were 525.6 hr*µg/ml (403.2, 762.0) and 83.7 (57.3, 129.5), respectively. For those on CRRT receiving the same dose, CAZ and AVI median (IQR) AUCs were 450.2 (450.0, 558.4) and 102.4 (100.7, 142.3), respectively. CAZ pharmacodynamics (PD) targets of 100% fT > 1x and 4x MIC were achieved in 90% and 55% of pts, respectively. AVI PD targets of 100% fT > 1 and 2.5µg/mL were achieved in 100% and 80% of pts, respectively. Treatment-emergent adverse events were not reported in any case. Ceftazidime and avibactam pharmacokinetic parameters among critically-ill patients Conclusion Among this cohort of critically-ill pts, CAZ and AVI exposures varied; however, most pts achieved PD targeted exposures, including those patients receiving CRRT and a standard dosing regimen of 2.5g IV q 8h. Disclosures Erin K. McCreary, PharmD, Entasis (Advisor or Review Panel member)Summit (Advisor or Review Panel member) Ryan K. Shields, PharmD, MS, Allergan (Advisor or Review Panel member, Research Grant or Support)Entasis (Advisor or Review Panel member)Melinta (Research Grant or Support)Menarini (Consultant)Merck (Advisor or Review Panel member, Research Grant or Support)Shionogi (Advisor or Review Panel member, Research Grant or Support)Summit (Advisor or Review Panel member)Tetraphase (Research Grant or Support)Venatorx (Advisor or Review Panel member, Research Grant or Support)

OXA-232 is an OXA-48-group class D β-lactamase that hydrolyzes expanded-spectrum cephalosporins and carbapenems at low levels. Clinical strains producing OXA-232 are sometimes susceptible to carbapenems, making it difficult to identify them in the clinical microbiology laboratory. We describe the development of carbapenem resistance in sequential clinical isolates of Raoultella ornithinolytica carrying bla(OXA-232) in a hospitalized patient, where the ertapenem MIC increased from 0.5 μg/ml to 512 μg/ml and the meropenem MIC increased from 0.125 μg/ml to 32 μg/ml during the course of ertapenem therapy. Whole-genome sequencing (WGS) analysis identified loss-of-function mutations in ompC and ompF in carbapenem-resistant isolates that were not present in the initial carbapenem-susceptible isolate. Complementation of a carbapenem-resistant isolate with an intact ompF gene resulted in 16- to 32-fold reductions in carbapenem MICs, whereas complementation with intact ompC resulted in a 2-fold reduction in carbapenem MICs. Additionally, bla(OXA-232) expression increased 2.9-fold in a carbapenem-resistant isolate. Rapid development of high-level carbapenem resistance in initially carbapenem-susceptible OXA-232-producing R. ornithinolytica under selective pressure from carbapenem therapy highlights the diagnostic challenges in detecting Enterobacteriaceae strains producing this inefficient carbapenemase.

The pharmacokinetics (PK) and dialytic clearance of isavuconazole in vitro and in 7 solid-organ transplant patients undergoing continuous renal replacement therapy (CRRT) were evaluated. In vivo, the mean (± standard deviation [SD]) plasma PK parameters of isavuconazole were as follows: maximum concentration of drug in serum (C(max)), 4.00 ± 1.45 mg/liter; minimum concentration of drug in serum (C(min)), 1.76 ± 0.76 mg/liter; half-life (t(1/2)), 48.36 ± 29.78 h; volume of distribution at steady state (V(ss)), 288.78 ± 182.11 liters, clearance at steady state (CL(ss)), 4.85 ± 3.79 liters/h; and area under the concentration-time curve (AUC), 54.01 ± 20.98 mg · h/liter. Transmembrane clearance represented just 0.7% of the total isavuconazole clearance. These data suggest that isavuconazole is not readily removed by CRRT and no dose adjustments are necessary.

We report 2 independent patients from whom carbapenem and ceftazidime-avibactam–resistant Enterobacter cloacae complex strains were identified. The ceftazidime-avibactam resistance was attributed to a 2–amino acid deletion in the R2 loop of AmpC β-lactamase, which concurrently caused resistance to cefepime and reduced susceptibility to cefiderocol, a novel siderophore cephalosporin.

In an infection with an Enterobacter sp. isolate producing Klebsiella pneumoniae Carbapenemase–4 and New Delhi Metallo-β-Lactamase–1 in the United States, recognition of the molecular basis of carbapenem resistance allowed for successful treatment by combining ceftazidime-avibactam and aztreonam. Antimicrobial synergy testing and therapeutic drug monitoring assessed treatment adequacy.

The carbapenem class of antibiotics is invaluable for the treatment of selected multidrug-resistant Gram-negative pathogens. The continued transmission of carbapenem-resistant bacteria such as ST258 K. pneumoniae is of serious global public health concern, as treatment options for these infections are limited. This genomic epidemiologic investigation traced the natural history of ST258 K. pneumoniae in a single health care setting over nearly a decade. We found that distinct ST258 subpopulations have caused both device-associated and ward-associated outbreaks, and some of these populations remain endemic within our hospital to the present day. The finding of virulence determinants among emergent ST258 clones supports the idea of convergent evolution of drug-resistant and virulent CRKP strains and highlights the need for continued surveillance, prevention, and control efforts to address emergent and evolving ST258 populations in the health care setting., Carbapenem-resistant Klebsiella pneumoniae (CRKP) strains belonging to sequence type 258 (ST258) are frequent causes of hospital-associated outbreaks and are a major contributor to the spread of carbapenemases. This genetic lineage emerged several decades ago and remains a major global health care challenge. In this study, genomic epidemiology was used to investigate the emergence, evolution, and persistence of ST258 carbapenem-resistant K. pneumoniae outbreak-causing lineages at a large tertiary care hospital over 8 years. A time-based phylogenetic analysis of 136 ST258 isolates demonstrated the succession of multiple genetically distinct ST258 sublineages over the 8-year period. Ongoing genomic surveillance identified the emergence and persistence of several distinct clonal ST258 populations. Patterns of multidrug resistance determinants and plasmid replicons were consistent with continued evolution and persistence of these populations. Five ST258 outbreaks were documented, including three that were caused by the same clonal lineage. Mutations in genes encoding effectors of biofilm production and iron acquisition were identified among persistent clones. Two emergent lineages bearing K. pneumoniae integrative conjugative element 10 (ICEKp10) and harboring yersiniabactin and colibactin virulence factors were identified. The results show how distinct ST258 subpopulations have evolved and persisted within the same hospital over nearly a decade.

Ceftazidime-avibactam (CAZ/AVI) combines ceftazidime with a diazabicyclooctane non-β-lactam β-lactamase inhibitor. This has potent inhibitory activity against KPC-type enzymes. We studied activity of clinically relevant regimens of CAZ/AVI against two KPC-2-bearing Klebsiella pneumoniae isolates (sequence type 258 recovered sequentially from the same patient) with and without ompK36 mutations in a hollow fiber infection model. The baseline total bacterial burden exceeded 109 CFU. For both isolates, there was early multi-log CFU/ml reductions in the bacterial burden for all regimens. Bacterial subpopulations with reduced susceptibilities to CAZ/AVI were isolated only from the no-treatment control arms. All CAZ/AVI regimens resulted in undetectable colony counts between days 6 and 8. At day 10, the total volume of each CAZ/AVI arm was plated, with no organisms recovered from any regimen, documenting complete eradication. A population model was fit to avibactam concentrations and total colony count outputs. The model fit was acceptable and demonstrated a large kill rate constant (K kill = 6.29 h-1) and a relatively low avibactam concentration at which kill rate was half maximal (C 50 = 2.19 mg/liter), concordant with the observed bacterial burden decline. A threshold analysis identified time > 4 mg/liter of avibactam as the index most closely linked to bacterial burden decline. Given the clinical outcomes seen with KPC-bearing organisms and the toxicities that occur when patients are treated with currently available polymyxins, drugs such as CAZ/AVI should have a prominent place in early therapy.

We report the case of a 61-year-old female with Crohn’s disease dependent on total parenteral nutrition who developed a central venous catheter bloodstream infection and septic arthritis, complicated further by osteomyelitis and persistent Candida glabrata fungemia. Fluconazole treatment led to persistent infection, and micafungin therapy failed with development of FKS -associated resistance. Infection responded after initiation of amphotericin B plus voriconazole.

We report the case of a 61-year-old female with Crohn’s disease dependent on total parenteral nutrition who developed a central venous catheter bloodstream infection and septic arthritis, complicated further by osteomyelitis and persistent Candida glabrata fungemia. Fluconazole treatment led to persistent infection, and micafungin therapy failed with development of FKS-associated resistance. Infection responded after initiation of amphotericin B plus voriconazole. Echinocandin resistance is increasingly recognized, suggesting a role for alternative antifungal therapies.

Ceftazidime-avibactam is used clinically in combination with a polymyxin for the treatment of carbapenem-resistant Gram-negative infections; however, there are limited data to support this practice. The objective of this study was to evaluate the activity of ceftazidime-avibactam and polymyxin B alone and in combination against Klebsiella pneumoniae carbapenemase (KPC)-producing Klebsiella pneumoniae in a tandem in vitro time-kill/in vivo Galleria mellonella survival model assay. Three KPC-3-producing K. pneumoniae clinical isolates were used for all experiments. All isolates harbored mutations in ompk35 and one isolate in ompk36; two isolates were susceptible to both ceftazidime-avibactam and polymyxin B, and one was resistant to both. Ceftazidime-avibactam was bactericidal against 2 of 3 strains at ≥2x minimum inhibitory concentration (MIC) whereas polymyxin B was not bactericidal against any strain at any concentration. Combinations at 1/4x or 1/2x MIC were not bactericidal or synergistic against any of the 3 isolates. In survival experiments, ceftazidime-avibactam at 4x MIC significantly improved larval survival over the untreated control strain whereas polymyxin B at 4x MIC did not. Combining polymyxin B with ceftazidime-avibactam at 4x MIC did not improve survival compared to ceftazidime-avibactam alone. This work indicates there is no improvement in in vitro bactericidal activity or in vivo efficacy when polymyxin B is combined with ceftazidime-avibactam against KPC-producing K. pneumoniae. This combination should be avoided in lieu of ceftazidime-avibactam alone or other potentially more efficacious, less toxic combination regimens.

We set out to assess feasibility and safety of allogeneic hematopoietic cell transplant in 17 persons with HIV in a phase II prospective multicenter trial. The primary endpoint was 100-day nonrelapse mortality (NRM). Patients had an 8/8 HLA-matched related or at least a 7/8 HLA-matched unrelated donor. Indications for transplant were acute leukemia, myelodysplasia, and lymphoma. Conditioning was myeloablative or reduced intensity. There was no NRM at 100 days. The cumulative incidence of grades II to IV acute graft-versus-host disease (GVHD) was 41%. At 1 year, overall survival was 59%; deaths were from relapsed/progressive disease (n = 5), acute GVHD (n = 1), adult respiratory distress syndrome (n = 1), and liver failure (n = 1). In patients who achieved complete chimerism, cell-associated HIV DNA and inducible infectious virus in the blood were not detectable. Blood and Marrow Transplant Clinical Trials Network 0903/AIDS Malignancy Consortium 080 was registered at www.clinicaltrials.gov (no. NCT01410344).

We report patient-to-patient transmission of Enterobacter hormaechei isolates with reduced susceptibility to ceftazidime-avibactam due to production of KPC-40, a variant of KPC-3 with a two-amino-acid insertion in the Ω-loop region (L167_E168dup). The index patient had received a prolonged course of ceftazidime-avibactam therapy, whereas the second patient had not received the agent and still became colonized with the KPC-40-producing strain. The complex dynamics of KPC (Klebsiella pneumoniae carbapenemase) described here highlight several key diagnostic and therapeutic considerations.

Ceftazidime-avibactam (CAZ/AVI) combines ceftazidime with a diazabicyclooctane non-β-lactam β-lactamase inhibitor. This has potent inhibitory activity against KPC-type enzymes. We studied activity of clinically relevant regimens of CAZ/AVI against two KPC-2-bearing Klebsiella pneumoniae isolates (sequence type 258 recovered sequentially from the same patient) with and without ompK36 mutations in a hollow fiber infection model. The baseline total bacterial burden exceeded 10(9) CFU. For both isolates, there was early multi-log CFU/ml reductions in the bacterial burden for all regimens. Bacterial subpopulations with reduced susceptibilities to CAZ/AVI were isolated only from the no-treatment control arms. All CAZ/AVI regimens resulted in undetectable colony counts between days 6 and 8. At day 10, the total volume of each CAZ/AVI arm was plated, with no organisms recovered from any regimen, documenting complete eradication. A population model was fit to avibactam concentrations and total colony count outputs. The model fit was acceptable and demonstrated a large kill rate constant (K(kill) = 6.29 h(−1)) and a relatively low avibactam concentration at which kill rate was half maximal (C(50) = 2.19 mg/liter), concordant with the observed bacterial burden decline. A threshold analysis identified time > 4 mg/liter of avibactam as the index most closely linked to bacterial burden decline. Given the clinical outcomes seen with KPC-bearing organisms and the toxicities that occur when patients are treated with currently available polymyxins, drugs such as CAZ/AVI should have a prominent place in early therapy.

Among 47 patients with urinary tract infections (UTIs) due to multidrug-resistant (MDR) bacteria, treatment with fosfomycin resulted in clinical cure rates of 87% and 94% at 48 hours and 14 days, respectively. Response rates did not vary across pathogens. Our retrospective, observational findings support fosfomycin treatment against MDR pathogens causing UTIs.

Meropenem-vaborbactam is a new agent with the potential to treat carbapenem-resistant Enterobacteriaceae (CRE) infections. We describe the in vitro activity of meropenem-vaborbactam against representative CRE genotypes and laboratory-engineered Escherichia coli isolates harboring mutant bla(KPC) genes associated with ceftazidime-avibactam resistance. We also compared disk diffusion and gradient strip testing methods to standard broth microdilution methods. Against 120 CRE isolates, median ceftazidime-avibactam and meropenem-vaborbactam MICs were 1 and 0.03 µg/ml, respectively. Ninety-eight percent (117/120) of isolates were susceptible to meropenem-vaborbactam (MICs ≤ 4 µg/ml). Against Klebsiella pneumoniae isolates harboring mutant bla(KPC), the addition of vaborbactam lowered the meropenem MICs in 78% of isolates (14/18); 100% were susceptible to meropenem-vaborbactam. Median meropenem-vaborbactam MICs were higher against K. pneumoniae carbapenemase (KPC)-producing K. pneumoniae isolates with mutant ompK36 porin genes (n = 26) than against those with wild-type ompK36 porin genes (n = 54) (0.25 versus 0.03 µg/ml; P

Background: Two recent trials showed a strong benefit of thrombectomy in the extended window. However, these studies were performed in selected centers and utilized strict inclusion criteria. We aim to evaluate the outcomes of thrombectomy in a large prospective cohort treated outside the rigid clinical trial setting. Methods: Trevo Registry patients with ICA, MCA-M1 or M2 occlusions and pre-morbid mRS0-2 were categorized according to time-from-last-seen-well (TLSW) to puncture as early (0-6hours) vs. late (6-24hours). Uni- and multivariate analyzes were performed to identify good outcome (90-day mRS0-2) predictors. Subgroup analyses were performed for the basic DAWN (age >=18, NIHSS >=10, ICA or M1 occlusion, pre-morbid mRS 0-1) and DEFUSE 3 (age 18-90, NIHSS >=6, ICA or MCA-M1 occlusion, mRS 0-2) trial criteria. Results: As compared to the late (n=430), early patients (n=1173) were older (70 vs 68, p=0.011) and had higher IV tPA use (69 vs 25%, p= 6 (1.37 [1.07-1.75]), DM (0.58 [0.44-0.77]), and time to treatment (0.98 [0.97-1.00]) were independent predictors of good outcomes. Imaging modality did not predict outcomes. Similar findings were observed in the early versus late DAWN-like (n=709 vs 257) and DEFUSE 3-like (n=855 vs 273) cohorts. There was great similarity between the outcomes of the Trevo Registry subsets vs their analogous RCTs: early DAWN-like vs SWIFT Prime (90-day mRS 0-2: 57.5 vs 60%; 90-day mRS 6: 11.% vs 9%), Late DAWN-like vs DAWN (50.2 vs 48.6%; 10.6 vs 18%), and Late DEFUSE 3-like vs DEFUSE 3 (52 vs 45%; 10.3 vs 14%). Conclusions: Our study provides favorable data for the generalizability of the safety and efficacy of thrombectomy in the “real-world” setting.

Although the Sensititre Yeast-One (SYO) and Etest methods are widely utilized, interpretive criteria are not available for triazole susceptibility testing of Candida or Aspergillus species. We collected fluconazole, itraconazole, posaconazole, and voriconazole SYO and Etest MICs from 39 laboratories representing all continents for (method/agent-dependent) 11,171 Candida albicans, 215 C. dubliniensis, 4,418 C. glabrata species complex, 157 C. guilliermondii (Meyerozyma guilliermondii), 676 C. krusei (Pichia kudriavzevii), 298 C. lusitaniae (Clavispora lusitaniae), 911 C. parapsilosis sensu stricto, 3,691 C. parapsilosis species complex, 36 C. metapsilosis, 110 C. orthopsilosis, 1,854 C. tropicalis, 244 Saccharomyces cerevisiae, 1,409 Aspergillus fumigatus, 389 A. flavus, 130 A. nidulans, 233 A. Niger, and 302 A. terreus complex isolates. SYO/Etest MICs for 282 confirmed non-wild-type (non-WT) isolates were included: ERG11 (C. albicans), ERG11 and MRR1 (C. parapsilosis), cyp51A (A. fumigatus), and CDR2 and CDR1 overexpression (C. albicans and C. glabrata, respectively). Interlaboratory modal agreement was superior by SYO for yeast species and by the Etest for Aspergillus spp. Distributions fulfilling CLSI criteria for epidemiological cutoff value (ECV) definition were pooled, and we proposed SYO ECVs for S. cerevisiae and 9 yeast and 3 Aspergillus species and Etest ECVs for 5 yeast and 4 Aspergillus species. The posaconazole SYO ECV of 0.06 g/ml for C. albicans and the Etest itraconazole ECV of 2 g/ml for A. fumigatus were the best predictors of non-WT isolates. These findings support the need for method-dependent ECVs, as, overall, the SYO appears to perform better for susceptibility testing of yeast species and the Etest appears to perform better for susceptibility testing of Aspergillus spp. Further evaluations should be conducted with more Candida mutants. Fil: Espinel-Ingroff, A.. Virginia Commonwealth University Medical Center; Fil: Turnidge, J.. University of Adelaide; Australia Fil: Alastruey-Izquierdo, A.. Centro Nacional de Microbiologia; Fil: Botterel, F.. Mycologie; Fil: Canton, Eduardo. Instituto de Investigación Sanitaria la Fe; Fil: Castro, C.. Hospital Universitario de Valme; Fil: Chen, Y.-C.. National Taiwan University Hospital; Fil: Chen, Y.. Public Health Ontario; Fil: Chryssanthou, E.. Karolinska University Hospital; Fil: Dannaoui, E.. Universite Paris Descartes; Fil: Garcia, Guillermo Manuel. Universidad Nacional del Litoral; Argentina Fil: Gonzalez, G.M.. Universidad Autónoma de Nuevo León; Fil: Govender, N.P.. University of the Witwatersrand; Sudáfrica Fil: Guinea, J.. Hospital General Universitario Gregorio Marañon; Fil: Kidd, S.. National Mycology Reference Centre; Fil: Lackner, M.. Medizinische Universitat Innsbruck; Fil: Lass-Flörl, C.. Medizinische Universitat Innsbruck; Fil: Linares-Sicilia, M.J.. Universidad de Cordoba, Facultad de Medicina; Fil: López-Soria, L.. Hospital Universitario Cruces; Fil: Magobo, R.. Universite Paris Descartes; Fil: Pelaez, T.. Hospital Universitario Central de Asturias; Fil: Quindós, G.. Universidad del Pais Vasco - Euskal Herriko Unibertsitatea, Campus Bizkaia; Fil: Rodriguez-Iglesia, M.A.. Universidad de Cádiz; España Fil: Ruiz, M.A.. Instituto de Investigación Sanitaria Aragón; Fil: Sánchez-Reus, F.. Hospital de la Santa Creu I Sant Pau; Fil: Sanguinetti, M.. Università Cattolica del Sacro Cuore, Rome; Fil: Shields, R.. University of Pittsburgh at Johnstown; Estados Unidos. University of Pittsburgh; Estados Unidos Fil: Szweda, P.. Gdan´ Sk University Of Technology; Fil: Tortorano, A.. Università degli Studi di Milano; Italia Fil: Wengenack, N.L.. Mayo Clinic In Rochester, Minnesota; Fil: Bramati, S.. Azienda Ospedaliera San Gerardo Monza; Fil: Cavanna, C.. Fondazione Irccs Policlinico San Matteo; Fil: DeLuca, C.. Humanitas Research Hospital; Fil: Gelmi, M.. Spedali Civili Di Brescia; Fil: Grancini, A.. Ospedale Maggiore Policlinico Milano; Fil: Lombardi, G.. Ospedale Niguarda, Milan; Fil: Meletiadis, J.. University Of Athens Medical School; Fil: Negri, C.E.. Universidade Federal de Sao Paulo; Fil: Passera, M.. Microbiology Institute; Fil: Peman, J.. Hospital Universitari I Politècnic la Fe; Fil: Prigitano, A.. Università degli Studi di Milano; Italia Fil: Sala, E.. Asst Lariana; Fil: Tejada, M.. Irccs Policlinico San Donato

Perioperative antimicrobial prophylaxis is administered to liver transplant (LTx) recipients to prevent surgical site infections (SSIs), but regimens are not standardized, and there are limited effectiveness data. Prevention and treatment of SSIs have been complicated by the emergence of multidrug-resistant (MDR) pathogens.We retrospectively reviewed SSIs among 331 LTx recipients at our center in 2010 to 2014.Culture-proven superficial and deep SSIs occurred in 3% and 15% of patients, respectively, at median 12.5 and 13.5 days post-LTx. Recipients with superficial SSIs and those without SSIs were similar in demographics, clinical characteristics, length of hospital stay, and mortality. Deep SSIs included abscesses (58%), peritonitis (28%), deep incisional infections (8%), and cholangitis (6%). Rates of deep SSIs were comparable among patients receiving prophylaxis with ampicillin-sulbactam, aztreonam and vancomycin, or tigecycline (P = 0.61). Independent risk factors for deep SSIs were bile leak (P0.001) and operative time (P0.001). Enterobacteriaceae (42%), Enterococcus spp. (24%), and Candida spp. (15%) were predominant pathogens. Fifty-three percent of bacteria were MDR, including 95% of Enterococcus faecium and 55% of Enterobacteriaceae; 82% of deep SSIs were caused by bacteria resistant to antimicrobials used for prophylaxis, and 58% of patients were treated with an inactive empiric regimen. Deep SSIs were associated with longer lengths of stay (P0.001), and higher 90-day and long-term mortality rates (P0.001).Deep SSIs, including those caused by MDR bacteria, were common after LTx despite prophylaxis with broad-spectrum antimicrobials. Rather than altering prophylaxis regimens, programs should devise empiric treatment regimens that are directed against the most common local pathogens.

Thirty-seven carbapenem-resistant Enterobacteriaceae (CRE)-infected patients were treated with ceftazidime-avibactam. Clinical success and survival rates at 30 days were 59% (22/37) and 76% (28/37), respectively. In 23% (5/22) of clinical successes, CRE infections recurred within 90 days. Microbiologic failure rate was 27% (10/37). Ceftazidime-avibactam resistance was detected in 30% (3/10) of microbiologic failures.

We compared the in vitro activities of gentamicin (GEN), tobramycin (TOB), amikacin (AMK), and plazomicin (PLZ) against 13 Enterobacter isolates possessing both Klebsiella pneumoniae carbapenemase and extended-spectrum β-lactamase (KPC+/ESBL+) with activity against 8 KPC+/ESBL−, 6 KPC−/ESBL+, and 38 KPC−/ESBL− isolates. The rates of resistance to GEN and TOB were higher for KPC+/ESBL+ (100% for both) than for KPC+/ESBL− (25% and 38%, respectively), KPC−/ESBL+ (50% and 17%, respectively), and KPC−/ESBL− (0% and 3%, respectively) isolates. KPC+/ESBL+ isolates were more likely than others to possess an aminoglycoside-modifying enzyme (AME) (100% versus 38%, 67%, and 5%; P = 0.007, 0.06, and P < 0.01 for all). KPC+/ESBL+ isolates also had a greater number of AMEs (mean of 4.6 versus 1.5, 0.9, and 0.05, respectively; P < 0.01 for all). GEN and TOB MICs were higher against isolates with >1 AME than with ≤1 AME. The presence of at least 2/3 of KPC, SHV, and TEM predicted the presence of AMEs. PLZ MICs against all isolates were ≤4 μg/ml, regardless of KPC/ESBL pattern or the presence of AMEs. In conclusion, GEN and TOB are limited as treatment options against KPC+ and ESBL+ Enterobacter . PLZ may represent a valuable addition to the antimicrobial armamentarium. A full understanding of AMEs and other aminoglycoside resistance mechanisms will allow clinicians to incorporate PLZ rationally into treatment regimens. The development of molecular assays that accurately and rapidly predict antimicrobial responses among KPC- and ESBL-producing Enterobacter spp. should be a top research priority.

Nafcillin and oxacillin are used interchangeably in clinical practice, yet few studies have evaluated the safety of these two agents. Our objective was to compare the differential tolerabilities of nafcillin and oxacillin among hospitalized patients. We conducted a retrospective cohort study of all patients who received 12 g/day of nafcillin or oxacillin for at least 24 h. Two hundred twenty-four patients were included. Baseline characteristics and comorbidities were similar among patients receiving nafcillin ( n = 160) and those receiving oxacillin ( n = 64). Hypokalemia, defined as a potassium level of ≤3.3 mmol/liter or ≤2.9 mmol/liter or as a ≥0.5-mmol/liter decrease from the baseline level, occurred more frequently among patients who received nafcillin (51%, 20%, and 56%, respectively) than among those who received oxacillin (17%, 3%, and 34%, respectively; P < 0.0001, P = 0.0008, and P = 0.005, respectively). By multivariate logistic regression analysis, receipt of nafcillin was an independent predictor of severe hypokalemia (odds ratio [OR] = 6.74; 95% confidence interval [CI], 1.46 to 31.2; P = 0.02). Rates of hepatotoxicity did not differ between groups; however, acute kidney injury occurred more commonly with nafcillin than with oxacillin (18% versus 6%; P = 0.03). Overall, 18% of patients who received nafcillin discontinued therapy prematurely due to adverse events, compared to 2% of patients who received oxacillin ( P = 0.0004). Nafcillin treatment is associated with higher rates of adverse events and treatment discontinuation than oxacillin among hospitalized adult patients. These findings have important implications for patients in both inpatient and outpatient settings, particularly patients who require long-term therapy and cannot be monitored routinely. Future randomized controlled studies evaluating the efficacy, costs, and tolerability of nafcillin versus oxacillin are warranted.

Aminoglycoside treatment of carbapenem-resistant (CR) Klebsiella pneumoniae bacteremia was associated with a 70% rate (23/33) of 30-day survival. Successful treatment was associated with sources of bacteremia amenable to reliable aminoglycoside pharmacokinetics ( P = 0.037), acute physiology and chronic health evaluation II (APACHE II) scores of P = 0.16), and nonfatal underlying diseases ( P = 0.015). Success rates were 78% and 100% if ≥2 and all 3 factors were present, respectively. Clinicians may consider the use of aminoglycosides against CR K. pneumoniae bacteremia if strains are susceptible and the sources of infection are amenable to reliable pharmacokinetics.

Ceftazidime–avibactam resistance among carbapenem-resistant Klebsiella pneumoniae at our hospital has emerged in sequence type (ST)-258, clade II isolates. We investigated hypermutability of ST258, clade II (n = 6) and clade I K. pneumoniae (n = 8) using a standard rifampin assay. Mutational frequencies were ≤10–7.1, indicating that isolates were not hypermutators. Mutational frequencies did not differ between clade II and I isolates. Ceftazidime–avibactam resistance among ST258, clade II K. pneumoniae is most likely a reflection of our hospital's ecology.

Background Recent randomized controlled trials show benefit of thrombectomy for large vessel occlusion in stroke. Real‐world data aid in assessing reproducibility of outcomes outside of clinical trials. The Trevo Retriever Registry is a multicenter, international, prospective study designed to assess outcomes in a large cohort of patients. Methods and Results The Trevo Registry is a prospective database of patients with large vessel occlusion treated with the Trevo device as the first device. The primary end point is revascularization based on modified Thrombolysis in Cerebral Infarction score and secondary end points include 90‐day modified Rankin Scale, 90‐day mortality, neurological deterioration at 24 hours, and device/procedure related adverse events. Year 2008 patients were enrolled at 76 centers in 12 countries. Median admission National Institutes of Health Stroke Scale was 16 (interquartile range, 11–20). Occlusion sites were internal carotid artery (17.8%), middle cerebral artery (73.5%), posterior circulation (7.1%), and distal vascular locations (1.6%). A modified Thrombolysis in Cerebral Infarction 2b or 3 was achieved in 92.8% (95% CI, 91.6, 93.9) of procedures, with 55.3% (95% CI, 53.1, 57.5) of patients achieving modified Rankin Scale ≤2 at 3 months. Patients meeting revised 2015 American Heart Association criteria for thrombectomy had a 59.7% (95% CI , 56.0; 63.4) modified Rankin Scale 0 to 2 at 3 months, whereas 51.4% treated outside of American Heart Association criteria had modified Rankin Scale 0 to 2. 51.4% (95% CI , 49.6, 55.4). Symptomatic intracranial hemorrhage rate was 1.7% (95% CI , 1.2, 2.4). Conclusions The Trevo Retriever Registry represents real‐world data with stent retriever. The registry demonstrates similar reperfusion rates and outcomes in the community compared with rigorous centrally adjudicated clinical trials. Future subgroup analysis of this cohort will assist in identifying areas of future research. Clinical Trial Registration URL : https://www.clinicaltrials.gov . Unique identifier: NCT 02040259.

Isavuconazole may be useful in treating and preventing fungal infections in solid organ transplant (SOT) recipients due to its safety profile and activity against Aspergillus and some Mucorales . Isavuconazole has favourable pharmacokinetics based on clinical trials in various patient populations, but data are limited in SOT recipients. We evaluated the steady state pharmacokinetics of Isavuconazole in 26 SOT recipients receiving the drug intravenously for prophylaxis. There was moderate inter-patient variability in isavuconazole pharmacokinetic parameters (coefficients of variation of 51% for area under the plasma concentration-time curve (AUC) and 59% for trough plasma concentration), which were in general less than previously reported for other mould-active azoles such as voriconazole and posaconazole. AUC and steady state trough plasma concentrations (C trough ) were significantly lower in women, patients with body mass index ≥18.5 kg/m 2 , and those receiving hemodialysis. Trough plasma concentrations were highly-correlated with AUCs (R 2 =0.94), and can serve as suitable measure of isavuconazole exposure in patients. In conclusion, moderate inter-patient variability in isavuconazole exposure, identification of factors associated with lower exposure, recognition that C trough is a surrogate marker for AUC and availability of a simple analytical method, suggest that therapeutic drug monitoring (TDM) may be useful for guiding treatment in at least some SOT recipients. Future studies are needed to correlate isavuconazole exposure with patients’ clinical outcomes, and to determine the clinical role of TDM.

Echinocandins are front-line agents for treatment of invasive candidiasis. There are no reported agent-specific differences in Candida mutational frequency of resistance or propensity to develop FKS mutations. The objective of this study was to measure spontaneous and FKS mutation rates among Candida glabrata strains. Twenty bloodstream isolates from patients with or without prior echinocandin exposure were included. Minimum inhibitory concentrations (MICs), minimum fungicidal concentrations (MFCs), and mutation prevention concentrations were higher for caspofungin than for anidulafungin (P 4-fold increases in MICs without FKS hot spot mutations; three of these harbored Fks2 mutations upstream of hot spot 1. The final isolate was FKS1 and FKS2 wild-type, but the 50% inhibitory concentrations of caspofungin and micafungin were increased 2.7- and 8-fold, respectively. In conclusion, micafungin may be superior in vitro to the other agents in limiting the emergence of resistance among C. glabrata. Caspofungin exposure may be most likely to promote resistance development. These data provide a foundation for future investigations of newly developed echinocandin agents.

We tested ceftazidime-avibactam and colistin against 24 carbapenem-resistant Enterobacteriaceae (CRE) isolates by time-kill studies. Ceftazidime-avibactam at 0.25×, 1×, and 4× the MIC was bactericidal against 8%, 21%, and 88% of the isolates, respectively. Colistin (2 μg/ml) was bactericidal against 83% (12 h) and 42% (24 h) of the isolates. In combination, synergy and antagonism were identified against 13% and 46% of the isolates, respectively. The combination did not suppress ceftazidime-avibactam resistance. Colistin plus ceftazidime-avibactam did not provide a benefit over ceftazidime-avibactam against most CRE isolates.

Ceftazidime-avibactam was used to treat 77 patients with carbapenem-resistant Enterobacteriaceae (CRE) infections at our center. Thirty- and 90-day survival rates were 81% and 69%, respectively; these rates were higher than those predicted by SAPS II and SOFA scores at the onset of infection. Clinical success was achieved for 55% of patients but differed by the site of infection. Success rates were lowest for pneumonia (36%) and higher for bacteremia (75%) and urinary tract infections (88%). By multivariate analysis, pneumonia ( P = 0.045) and receipt of renal replacement therapy (RRT) ( P = 0.046) were associated with clinical failure. Microbiologic failures occurred in 32% of patients and occurred more commonly among patients infected with KPC-3-producing CRE than among those infected with KPC-2-producing CRE ( P = 0.002). Pneumonia was an independent predictor of microbiologic failure ( P = 0.007). Ceftazidime-avibactam resistance emerged in 10% of patients, including 14% of those infected with Klebsiella pneumoniae and 32% of those with microbiologic failure. RRT was an independent predictor of the development of resistance ( P = 0.009). Resistance was identified exclusively among K. pneumoniae bacteria harboring variant KPC-3 enzymes. Upon phylogenetic analysis of whole-genome sequences, resistant isolates from 87.5% (7/8) of patients clustered within a previously defined sequence type 258 (ST258) clade II sublineage; resistant isolates from one patient clustered independently from other ST258 clade II isolates. In conclusion, our report offers new insights into the utility and limitations of ceftazidime-avibactam across CRE infection types. Immediate priorities are to identify ceftazidime-avibactam dosing and therapeutic regimens that improve on the poor outcomes among patients with pneumonia and those receiving RRT.

Background and Aims: Balloon Guide Catheter (BGC) use during thrombectomy treatment in Stroke patients has been reported to have positive effects on revascularization, procedural characteristics, and clinical outcomes. We evaluate the use of BGC in an open-label large prospective TREVO Retriever Registry of real world patients to determine predictors of good ‘clinical’ outcomes. Method: Consecutive Trevo Registry patients that had Balloon Guide Catheter (BGC) used during their thrombectomy procedure were identified; a subset of patients who fulfilled the criteria (ICA and/or MCA-M1/M2 occlusion with pre-morbid mRS 0-1, TLSW ≤6 hrs) within the cohort were also identified. Multivariate analysis was performed to identify the predictors of good outcomes in BGC thrombectomy patients. Results: A total of 1031 BGC treated Trevo Registry patients (overall enrolled, n=2010) qualified for analysis, of which 605 patients fulfilling the subset criteria were identified. The mean age of BGC/stent retriever patients was 67.5 with a median (IQR) baseline NIHSS of 15(11-19). Occlusion location of the BCG group was ICA -20.4%, M1- 57.1%, M2/M3-20.3%, and Posterior 1.8%. In the overall BGC cohort, the median (IQR) time to treatment was (4.2 (3.0,6.5)- hrs.) with conscious/local sedation used in 63.4% and general anesthesia used in 37.3% of cases. The median number of passes with Trevo stent retriever was 1 and revascularization (mTICI ≥ b) was achieved in 92.8% of cases. The sICH rate was low at 1.9% (20/1031) with a low rate of vessel perforation (0.2%). At 90 days post stroke, 56.0% of patients achieved functional independence (mRS 0-2) with 63.7% of the subset of “guidline “ BGC patients achieving functional independence at 90 days. Multivariate logistic regression showed age (aOR 0.97 [0.96, 0.99] P Conclusion: Data from Trevo Registry demonstrate the use of BGC in thrombectomy procedure is safe, and leads to a reduction of disability in ischemic stroke patients.

Background: Endovascular therapy (EVT) effectiveness is established in ischemic strokes with large vessel occlusion (LVO) in the terminal ICA and M1, which was extended up to 24 hrs by recent DAWN trial results. However this benefit is not as well established in more distal (M2) occlusions, especially late presenters (beyond 6 hrs). We evaluated thrombectomy outcomes in M2 occlusions as compared to ICA/M1 across early and late time windows. Methods: In a prospective, multicenter, single arm, international registry (Trevo Retriever Registry), anterior circulation LVOs were stratified on clot location into M2 vs ICA/M1 and dichotimized into early vs late (0-6 vs 6-24 hrs). 90 day mRS (0-1 excellent, 0-2 good) were the primary outcomes; sICH and dissection were the secondary (safety) outcomes. Multivariate analyses identified pre-procedure variables independently correlating with good outcome in M2s. Results: 1581 patients were identified (1265 ICA/M1, 316 M2). The M2 and ICA/M1 groups were similar (age in both 68.4), IV-tPA (69.1 vs 69.7%, p=0.8) and same median/IQR ASPECTS 8 (7-9). M2 patients had lower NIHSS (13 vs 16, p Conclusion: Excellent and good outcomes may be achieved in distal LVO isolated to M2 similar to those with proximal occlusions. A benefit that can be reached up to 24 hrs.

Background and Aims: Intravenous tPA remains the standard of care, with MT currently indicated within 8 hours for IV tPA failures or patients with IV tPA contraindications. Whether LVO patients should receive IV tPA treatment or instead be triaged directly to MT therapy is currently unknown but greatly debated. The Trevo Registry is a real world, multi-center, international study of mechanical thrombectomy (MT) patients treated from 0-24 hours. Evaluation of the Trevo Registry clinical and procedurals outcomes of MT patients treated with or without IV tPA could provide insight into the benefit of IV tPA in MT patients. We hypothesized that in MT patients treated within 8 hours, pretreatment with intravenous tPA would lead to better clinical outcomes compared to patients who did not receive IV tPA. Method: Consecutively enrolled patients treated within 8 hours with ICA, M1, or M2 occlusions were selected for analysis. Univariate and multivariable regressions were conducted to identify clinical and radiographic independent variables that correlate best with the dependent variable of functional outcome: mRS 0-2, with a focus on intravenous tPA treatment. Results: A total of 1183 Trevo Registry patients (overall enrolled, n=2010) qualified for analysis, of whom 380 were not treated with IV tPA. Demographics were similar, however atrial fibrillation (46.3% vs 27.2%) and previous ischemic stroke (14.1% vs 7.5%) were higher in the no IV tPA group. The median time to treatment was similar (3.8 vs. 3.6 hrs). First pass mTICI ≥ 2B (63.6% vs 66.4%) and final revascularization (91.1% vs 92.8%) were similar between no IV tPA and IV tPA groups.Unadjusted, there were similar rates of functional outcome (90 day mRS 0-2; 60.9% vs. 62.5%). After adjustment, patients who did not receive IV-tPA had similar rates of good outcome (aOR 1.08, 95% CI [0.87-1.34]. P=0.58) as well as reduction (shift) in disability (aOR 1.08, 95% CI [0.87-1.34]. P=0.49). Safety outcomes (mortality, sICH) were similar between both groups. Conclusion: In the Trevo Registry of MT patients treated within 8 hours, patients who did not receive IV tPA had similar endovascular and clinical outcomes as patients pretreated with IV tPA. The added benefit of IV tPA for MT patients should be further investigated.

Background: The DAWN trial showed EVT effectiveness in the late time window (6-24 hrs), however, DAWN patients were carefully selected based on advanced perfusion imaging, CTP and MRI. Similar to the early window (0-6 hrs), simple imaging (CT) and other clinical variables may select patients for thrombectomy beyond 6 hours. We evaluated a largescale, real world practice for predictors that could identify patients who may benefit from EVT in the late time window. Methods: Patients with LVO in the anterior circulation (M1, M2, ICA) from a prospective, single arm, multicenter, international registry (Trevo Retriever Registry) treated in the late window LSN to groin puncture (GP) (6-24 hrs) were included. Univariate and multivariate analyses assessed factors independently correlating with good outcome (90 day mRS 0-2). Furthermore, patients outcomes were compared based on their baseline imaging selection CT vs CTP and MRI. Results: 549 patients were treated beyond 6 hours. The average age was 67, median/IQR ASPECTS 8(6-9), median/IQR NIHSS was 15 (9-20), median/IQR time LSN to GP (hr) was 9.7 (7.3-13.6) and IV-tPA rate were 22.8%. CT was the only imaging selection method in 15.9%, while additional advanced imaging was utilized in the remaining patients; CTP (70%), and MRI(14.1%). Good outcomes were observed in 51.4% of late window patients. Age (aOR 0.96, 95% CI 0.94-0.98, p Conclusion: Simple imaging and clinical variables can identify patients that could benefit from thrombectomy in the late window. Importantly, ASPECTS reliably predicted good outcome beyond 6 hours without adjunctive benefit from adding advanced perfusion imaging, a finding that may simplify patients selection to facilitate and generalize the intervention in the late window to wide, real world practice.

Background IFI is a significant complication following lung transplant (LT). VOR was universal antifungal px in our LT program from 2004 to October 2015, at which time px was changed to ISA. We compared the efficacy and tolerability of VOR vs. ISA px in LTR. Methods We reviewed all LTR from September 2013 to February 2018 who received VOR or ISA Px. The standard duration of px was 3 or 4 months following basiliximab and alemtuzumab induction, respectively. All patients were followed for ≥1 years post-Tx. IFI was defined by revised EORTC/MSG criteria. Results In total, 310 LTR were included, 149 and 161 of whom received ISA and VOR px, respectively. There was no difference in demographics, underlying diseases, single vs. double LT, or induction therapy (alemtuzumab vs. basiliximab) between the 2 groups. At 1-year after LT, 9% (14) and 8% (13) of patients in ISA and VOR groups developed IFI, respectively (P = 0.5). 5% (7) and 3% (5) of patients developed breakthrough (BT) IFI during ISA and VOR px, respectively (P = 0.6; Figure 1, P = 0.4, Kaplan-–Meier). ISA BT included pneumonia (PNA, 2), endobronchial IFI (2), mediastinitis (1), chest wall IFI (1), and candidemia (1). ISA BT patients were infected with Aspergillus fumigatus (3; 2 with ISA MIC = 0.5 µg/mL, 1 MIC = 1 µg/mL), black mould (1), and yeasts (3; 2 C. glabrata, 1 C. albicans). VOR BT IFI included PNA (2), endobronchial IFI (1), empyema (1), and chest wall IFI (1). VOR BT IFIs were due to A. ustus, A. niger, A. lentulus, black mould, and Rhizopus spp (1 each). All Aspergillus VOR BT isolates exhibited VOR MIC ≥2 µg/mL. Patients with IFI were more likely to have positive pre-LT respiratory fungal culture (P = 0.01) and grade ≥3 ischemic reperfusion injury (IRI) post-LT (P = 0.01). VOR and ISA were prematurely discontinued in 53% (85) and 14% (21) of patients due to adverse events, respectively (P < 0.0001). Hepatotoxicity was more common with VOR (22%, 35) than ISA (5%, 7) (P < 0.0001). IFI was an independent risk factor for death at 1 year (Figure 2, P < 0.0001, Kaplan–Meier). Conclusion ISA was as effective as VOR in preventing IFI in LTR, and significantly better tolerated. Pre-LT fungal culture positivity and grade ≥3 IRI post-LT were risk factors for the development of IFI. IFI within 1-year post-LT had a significant impact on mortality Disclosures Fernanda P. Silveira, MD, MS, FIDSA, Ansun: Grant/Research Support; Qiagen: Grant/Research Support; Shire: Grant/Research Support; Whiscon: Grant/Research Support.

Background The majority of bacterial BSIs are believed to stem from a single, clonal organism. We hypothesized that most CRK BSIs are caused by genetically diverse, clonal strains that exhibit different phenotypes. Methods Blood cultures (BCs) that were positive for CRK from each of 10 patients (patients) were streaked onto agar plates, and 100 individual colonies were chosen for Illumina whole-genome sequencing. Strains from 3 patients were tested for in vitro phenotypes and virulence in mice. Results Patients had BSIs due to ST258 K. pneumoniae (Kp; 6), non-ST258 Kp (3), and K. michiganensis (Km; 1). 5 patients were infected with strains that differed by core genome single nucleotide polymorphism phylogeny (2–5 unique genotypes/patient) [figure]. 6 patients were infected with strains that differed by gene or plasmid content, and/or gene deletions [table]. Differences in individual patients encompassed antibiotic resistance and putative virulence genes (including mixtures of blaKPC+ and blaKPC– strains, and various capsular (CPS) and porin mutant strains). In total, BSIs in 8 of 10 patients were caused by a genotypically diverse population. In each of 3 patients, genotypically diverse ST258 Kp strains demonstrated significant differences in antibiotic susceptibility, CPS content, mucoviscosity, adherence, resistance to serum killing, and mortality rates and tissue burdens during BSIs of mice. ST258 strains from a pt with and without a KPC-bearing IncFIA plasmid differed in β-lactam susceptibility, but were equally virulent. Progressive loss of CPS in ST258 strains from another patient enhanced serum killing and adherence, and attenuated virulence. Using PCR markers to test 96 colonies per positive BC bottle, we demonstrated that strains selected by the clinical micro lab accounted for 2% to 98% of a population in different patients. Conclusion CRK causing BSIs in most patients demonstrated remarkable genotypic diversity, which impacted antibiotic susceptibility, virulence and other phenotypes. Differences were not recognized during hospitalization since clinical labs select single, morphologically distinct colonies for evaluation. Studies are needed to understand the clinical implications of our findings, diversity during other BSIs, and whether clinical lab practices need revision. Disclosures All authors: No reported disclosures.