bluuebunny/crossref_metadata_2025_split huggingface dataset:
603. Comparing assays for Clinical Phage Microbiology in biofilm
Authors: Rimon Amit , Coppenhagen Shunit , Nir-Paz Ran , Hazan Ronen 
Published: December 2022

Abstract

Background
Non-resolving infections are commonly associated with bacterial biofilm formation. One promising solution is the use of lytic bacterial bacteriophages, as an adjunctive approach with antibiotics to penetrate biofilms and cure infections.
A major challenge in the use of phages for therapy is the need for accurate personal matching of the most effective phage-antibiotic combination against the target bactera. This matching, termed “Clinical Phage Microbiology” (CPM) is even more problematic regarding biofilm and there are no standard methods for that. Here we compared several approaches for CPM in biofilms.

Methods
The efficacy of phages on the biofilm was tested in 8 methods using 5 phages at two concentrations. To this end five Pseudomonas aeruginosa (PA) specific phages were grown for biofilm establishment. Next, we followed the metabolic activity of the cultures using: (1)Agilent Seahorse XF Analyzers., and (2) Symcel’s calScreener calorimeter. In addition, we measured the levels of extracellular DNA in the biofilm supernatant using (3) rtPCR and (4) online by SYBR Green without amplification. The 5th method used GFP PA14 with an allure-red dye that allows the assessment of the adherent bacteria only. Last, we used the commonly used (6) Colony Forming Units (CFU) counts, (7) Crystal Violet (CV), and (8) Live/dead stain as our gold standard controls.

Results
Out of these methods, the calScreener (Figure 1A-F), and Seahorse were able to differentiate between phages real-time. The calSreener also showed a clear difference between biofilm and planktonic growth curves. The Real-Time PCR and the Live dead stain methods have shown a significant differentiation at the treatment endpoint. The other methods, CFU, CV, Syber Green, and Allura red did not show a significant difference between the phages. It should be noted that phages biofilm ranking did not correlate with the planktonic one. Figure 1
heat flow was measured using calScreener over 21 hours, comparing 5 different phages at a PFU of 108 and 106 on Pseudomonas aeruginosa planktonic (A) or biofilm (B-F). (A) planktonic bacteria and PASA16 phage treated, (B) KLEIN 3 phage, (C) PASA16 phage, (D) PB2F phage, (E) D9 phage, (F) PB2C phage. Figure 2
Comparison, using rtPCR, of 5 different phages at a PFU of 10^8 and 10^6 treated for 24 hours, and then their supernatant was filtered. Primers for housekeeping genes (A) ldhD, (B) rpoD.

Conclusion
We have compared 8 different methods as assays for phage screening. In this model of PA biofilm and phages, we found that calScreener and Seahorse are superior while CFU, CV, Syber Green, Allura red are not as useful.

Disclosures
Ran Nir-Paz, MD, BiomX: Advisor/Consultant|Technophage: Advisor/Consultant.
606. Efficacy and Safety of Ceftazidime-Avibactam Comparative Dosage Regimens in Patients with Kidney Injury: A Retrospective Cohort Study
Authors: Sait Walaa Adel , Damfu Nader , Aljefri Doaa , Esmail Sherine , Alhamdan Hani 
Published: December 2022

Abstract

Background
Limited data are available for Ceftazidime-avibactam (CAZ AVI) dosing in patients with chronic kidney diseases. High rate of treatment failure was found among patients with chronic kidney diseases for which renally adjusted doses has been used(1). In our institution, higher than labeled adjusted dosing regimens (HLAD) has been used for the treatment of severe infections. Doses were driven from ceftazidime adjusted dosing regimens in CKD patients. Therefore, we aimed to compare the efficacy and safety between labeled and HLAD regimens of CAZ-AVI in CKD patients.

Methods
A retrospective cohort study conducted between June 2018 and December 2020 in a tertiary hospital in Saudi Arabia, Jeddah. Patients ≥ 14 years old who received at least 48 hours of CAZ-AVI and have chronic kidney disease or on dialysis were included. The primary outcome was to assess the clinical cure of the HLAD group compared to labeled adjusted doses (LAD) group and defined as complete or partial resolution of fever and leukocytosis at the end of CAZ-AVI course. The secondary outcome was 30-day-mortality secondary to infections and recurrent of infections. Fisher's exact, chi-square test and contingency table analysis were used as appropriate.

Results
A total of 75 patients were included, 40 patients (46.7%) received HLAD. Fifty percent of the patients were on hemodialysis during CAZ-AVI course (n=38, 50%). The majority of our patients were in ICU (n=48, 64%). Clinical cure was relatively the same among the two groups with no statistical difference (57% with higher dose and 66%, 0.095 (-0.31-0.12), P=0.39). The number of 30-day mortality secondary to infection was higher (n=48, 64%) among the HLAD group compared to LAD group (74.2% and 55% respectively). Recurrence of infection were low in this study, which can be explained by the high rates of mortality, however, it was higher among patients who received LAD.

Conclusion
The efficacy and safety of both regimens of CAZ-AVI dosing were comparable and was not statistically significant in renally impaired patients. Larger studies are needed, however, to answer the study question on the use of higher than labeled adjusted dosing.
Reference:
Shields RK, Nguyen MH, Chen L, Press EG, Kreiswirth BN, Clancy CJ. Pneumonia and renal replacement therapy are risk factors for ceftazidime-avibactam treatment failures and resistance. Antimicrob Agents Chemother. 2018;62(5)

Disclosures
All Authors: No reported disclosures.
607. Establishing Pharmacokinetic Profile of β -lactams in Critically Ill Patients on Continuous Sustained Low-efficiency Dialysis (C-SLED)
Authors: Shah Madiha , Horton Matthew , Donnelley Monica 
Published: December 2022

Abstract

Background
Critically ill patients have altered pharmacokinetic (PK) due to severity of illness and multi-organ failure. The lack of pharmacokinetic and pharmacodynamic data in Continuous Sustained Low-efficiency Dialysis (C-SLED) further perpetuates the uncertainty of efficacy with current antimicrobial dosing strategies. The objective of this study is to evaluate patient-specific PK of various β-lactams antibiotics in critically ill patients on C-SLED to assess if the current dosing strategy leads to therapeutic drug levels.

Methods
This prospective observational cohort study was performed at an academic medical center from November 2021 to June 2022. It included patients age &gt; 18 years and on β-lactam antibiotics while on C-SLED. Therapeutic drug monitoring (TDM) was performed by checking two levels (peak and trough). These levels were used to calculate patient-specific elimination rate constant (k), half-life, and the fraction of time above MIC (fT&gt;MIC). Other data collected included demographics, β-lactam regimens, source of infection, microbiology data, mortality on days 7 and 30, and length of stay. Descriptive statistics were used for data analysis.

Results
There were 11 patients included in the study with a median age of 55 and 82% (n = 9) of patients were male. β-lactam daily regimen was dosed as creatinine clearance (CrCl) &gt; 50mL/min in 71.4% of patients (n = 10), CrCl 30-50 mL/min in 28.5% (n = 4), and &lt; 30mL/min in 0% of patients. An extended infusion dosing strategy was used in 35.6% of patients (n = 5). The therapeutic drug target (50%fT &gt; MIC for penicillins, 60%fT &gt; MIC for cephalosporins, 40%fT &gt; MIC for carbapenems) was achieved in 100% (n=14) of patients. Dose adjustment was not needed in all 14 cases. However, 100%fT &gt; MIC was only achieved in 64% (n=9) patients. The median hospital length of stay was 60 days. Mortality on days 7 and 30 was 9% (n=1) and 27% (n=3), respectively.

Conclusion
Preliminary analysis shows that β-lactam daily dose based on CrCl of &gt;30mL/min leads to therapeutic drug levels in patients on C-SLED.

Disclosures
All Authors: No reported disclosures.
614. Pharmacodynamics (PD) of the Beta-Lactamase Inhibitor Xeruborbactam When Administered as the Oral Prodrug in Combination with Ceftibuten
Authors: Tarazi Ziad , Roos Niki , Page Ted , Griffith David 
Published: December 2022

Abstract

Background
Xeruborbactam (XERU) is a member of a new class of cyclic boronic acid β-lactamase inhibitors with inhibitory activity against major members of Class A, B, C, and D beta-lactamases. XERU is highly orally bioavailable when administered as the isobutyryloxymethyl prodrug, with a long terminal plasma half-life that supports once daily dosing. The purpose of these studies was to determine the pharmacodynamic parameter that best described the activity of XERU administered as the oral prodrug in combination with a fixed dosage regimen of ceftibuten in the neutropenic mouse thigh infection model.
%24h Free Xeruborbactam Time &gt; 4 mg/L
24h Free Xeruborbactam AUC

Methods
Three E. coli and five K. pneumoniae isolates were used in these studies. Ceftibuten MICs (with 4 mg/L XERU) ranged from 0.125 to 2 mg/L and included strains with ESBLs and KPC. Mice were rendered neutropenic, infected with ∼107 CFU/thigh and were treated with various doses of XERU in combination with ceftibuten (50 mg/kg q6h) by the PO route starting 2 hours post infection for 24 hours. The ceftibuten dosage regimen was designed to simulate once daily 800 mg oral doses in humans obtained from a previous Phase 1 study. Plasma exposures (PK) were measured in neutropenic, infected mice. The relationship between PK-PD indices and the reduction in the log number of CFU per thigh were analyzed by using the sigmoid maximum (Emax) PD model.

Results
The activity of xeru was best described by the % 24h free xeru plasma concentrations exceeded 4 mg/L and 24h free XERU plasma AUC.
Xeru PK-PD Parameters in Combination with Ceftibuten

Conclusion
The PK-PD of XERU administered as the oral prodrug in combination with ceftibuten, and the clinical PK of both drugs support once-daily dosing for the treatment of cUTIs due to Enterobacterales, including ESBL- and carbapenemase-producing strains.

Disclosures
Ziad Tarazi, Qpex Biopharma: Employee Niki Roos, n/a, Qpex Biopharma: Employee Ted Page, n/a, Qpex Biopharma: Employee David Griffith, n/a, Qpex Biopharma: Employee.
635. Is Azole Prophylaxis in Liver Transplant Recipients Effective in Preventing Invasive Candidiasis in the Era of Emerging Resistance?
Authors: Gurram Pooja R , Silveira Fernanda P , Kwak Eun Jeong , Clancy Cornelius , Nguyen Minh-Hong 
Published: December 2022

Abstract

Background
Antifungal prophylaxis (px) in liver transplant (LT) recipients reduces invasive candidiasis (IC) and its associated mortality. Studies from our institution (UPMC) and others have shown that targeted px was as effective as universal px. Antifungal resistance has emerged among Candida spp., with ∼7% of the bloodstream isolates tested at CDC resistant to fluconazole. We sought to determine if our targeted antifungal px in LT recipients remained effective in the era of rising azole resistance.

Methods
We performed a retrospective study of patients undergoing LT at UPMC between 11/2010 and 06/2021. IC episodes were included if they occurred within 6 months of transplant. IC was defined using EORTC/MSGERC criteria, 2020. CLSI’s M60 2nd edition was used for antifungal susceptibility interpretation. Px was with fluconazole or voriconazole, based on risk factors for yeast or mold infection, respectively (Fig. 1).

Results
1065 patients (pts) underwent LT over the study period. The most common indications for LT were HCC and NASH cirrhosis. Thirty-four pts (3%) developed IC within six months. 74% and 65% of these pts had risk factors for yeast or mold infection at some point, respectively (Table 1). Twenty-five of 34 (73.5%) pts received antifungal px, with voriconazole most commonly. Sixteen pts with IC (47%) had living donor transplant, and 11 (32%) had Roux-en-Y anastomosis. Types of IC were intra-abdominal candidiasis in 19 (56%), fungemia in 11 (32%), and intra-abdominal IC with secondary fungemia in 4 (12%). Seventeen (50%) episodes were breakthrough (BT) IC (most BT occurred in the voriconazole group), eight (24%) developed after stopping px, and nine (26%) occurred in those without px (Table 2). C. albicans and C. glabrata were the most common species (Fig. 2). Sixteen isolates underwent susceptibility testing: 12% and 44% were resistant and S-DD to fluconazole (Fig. 2); none were resistant to voriconazole. Attributable mortality of IC was 8%.

Conclusion
Targeted antifungal px in LT recipients with fluconazole or voriconazole effectively prevented IC, even in the era of rising azole resistance among Candida spp. We recommend antifungal susceptibility testing for Candida spp. obtained from infected sites to guide antifungal therapy.

Disclosures
Fernanda P. Silveira, MD, Ansun: Grant/Research Support|Janssen: Honoraria|Merck: Grant/Research Support|Novartis: Grant/Research Support|Regeneron: Grant/Research Support|Takeda: Advisor/Consultant|Takeda: Grant/Research Support.
639. Vaccination in Kidney Transplant Candidates
Authors: Gajurel Kiran , Ngo Tue , McCurdy Lewis 
Published: December 2022

Abstract

Background
Kidney transplant (KT) candidates have historically low immunization rates against recommended vaccines. A retrospective study of KT candidates was conducted to assess contemporary vaccination rates and vaccine uptake during pre-transplant evaluation.

Methods
All KT candidates ≥ 18 years referred to Transplant Infectious Disease Clinic for pre-transplant evaluation between January 1, 2020 and August 31, 2020 were retrospectively studied for history of prior vaccination against Tdap, 13 valent pneumococcal conjugate vaccine (PCV13), 23 valent pneumococcal polysaccharide vaccine (PPSV23), Hepatitis A and B (using Hepatitis A total IgG and Hepatitis B surface antibodies as surrogate markers) and recombinant zoster vaccine (RZV). Seropositivity (as a marker of immunity) against measles, mumps, rubella and varicella was also assessed.

Results
109 KT candidates were evaluated (tables 1 & 2). Rates of prior vaccination against Tdap, PCV13 and PPSV23 were 33%, 58%, and 67%. Only 5 (8%) of 61 patients ≥ 50 years of age had received 2 doses of RZV. Thirty (28%) had positive Hepatitis A total IgG and 72 (66%) patients had a positive Hepatitis B surface antibody. Among 37 patients with negative Hepatitis B surface antibody, most had received at least one dose of Hepatitis B vaccine (five were non responders, 19 had had initiated the vaccine series and one had waning antibody response). 79-96% patients had immunity against measles, mumps, rubella and varicella. Patients ≥ 50 years (vs under 50 years) had numerically higher immunization rates against PCV13 and PPSV23 (67% vs 46% and 74% vs 58%) and higher rates of immunity against measles, mumps, rubella and varicella (95% vs 73%; 85% vs 69%, 95% vs 81% and 100% vs 92% respectively). Dialysis patients had a higher Hepatitis B surface antibody compared to non-dialysis patients (78% vs 39%).
Only 6 of 109 patients were fully immunized. Among 103 vaccine eligible patients, 99 (96%) agreed to get vaccinated. Table 1Baseline characteristics of kidney transplant candidates
Table 2 Vaccination in kidney transplant candidates

Conclusion
KT candidates have low rates of prior immunization against Tdap, PCV13, PPSV23, Hepatitis A and B and RZV but high rates of serological immunity against measles, mumps, rubella and varicella. The vaccine uptake during pre-transplant evaluation was high and it provides an unique opportunity to improve immunization in this population.

Disclosures
All Authors: No reported disclosures.
665. Modified Superposition in vitro Susceptibility of Aztreonam and Ceftazidime/Avibactam for an NDM-5 Metallo-β-Lactamase-Producing Klebsiella pneumoniae Isolate
Authors: Schmetterer Justin , Merrick Kelley , Gallegos Antonio , Babiarz Taylor , Lin Yao 
Published: December 2022

Abstract

Background
We describe a novel in vitro susceptibility testing approach of aztreonam and ceftazidime/avibactam using a superposition method paired with confirmatory testing and molecular sequencing of a New Delhi metallo-β-lactamase (NDM)-5-producing Klebsiella pneumoniae.

Methods
A modified strip superposition method with Epsilometer test (Etest) strips and Kirby Bauer disks was utilized to test the in vitro activity of aztreonam and ceftazidime/avibactam against the NDM-producing K. pneumoniae. The isolate was also sent for whole genome sequencing and tested for the in vitro activity of aztreonam and ceftazidime in combination with avibactam using a broth microdilution checkerboard assay.
Aztreonam and ceftazidime/avibactam in vitro testing with modified superposition method

Results
All zones of inhibition from the Etest superposition method were measured to be 22 mm in diameter (Clinical and Laboratory Standards Institute [CLSI] zone of inhibition for aztreonam susceptibility is ≥ 21 mm for Enterobacterales). The results of whole genome sequencing showed the K. pneumoniae isolate carried a metallo-β-lactamase (blaNDM-5), extended-spectrum β-lactamase (blaCTX-M-15), and other β-lactamases (blaSHV-11, blaTEM-1). Through the broth microdilution checkerboard method, the isolate demonstrated inhibition by aztreonam/avibactam (fixed concentration of 4mg/L) at a minimum inhibitory concentration (MIC) of 0.25 mg/L but was resistant to ceftazidime/avibactam (MIC &gt; 16 mg/L) and aztreonam alone (MIC &gt; 16 mg/L) according to CLSI breakpoints.

Conclusion
The in vitro activity of aztreonam and ceftazidime/avibactam against an NDM-5-producing K. pneumoniae was demonstrated with a modified superposition method. This may serve as a simplistic and readily available technique for rapidly determining antimicrobial activity in these difficult to treat pathogens.

Disclosures
Justin Schmetterer, PharmD, PhC, BCIDP, AbbVie Speaker Bureau: Honoraria Yao Lin, MS, Abbvie Inc: employee|Abbvie Inc: Stocks/Bonds.
893. Clinical Risk Score for Prediction of Invasive Candidiasis to Guide Empiric Echinocandin Therapy
Authors: Braham Mary Jane , Freeman Lauren K , Fang Wei 
Published: December 2022

Abstract

Background
Current treatment guidelines for invasive candidiasis (IC) largely recommend an echinocandin as initial therapy. Echinocandins have demonstrated non-inferiority to previously utilized agents for the treatment of IC with low toxicity, few drug-drug interactions, and activity against azole-resistant Candida species. Although echinocandins are suggested empirically when IC is suspected, recommendations for empiric therapy based upon IC risk factors do not exist. The primary objective is to develop a risk score to predict probability of IC to help triage when empiric therapy with an echinocandin is likely warranted.

Methods
This evaluation is a retrospective, case-control design of hospitalized adults that received at least one dose of micafungin between July 1, 2020 and June 30, 2021 for proven or suspected IC at a large academic medical center. Descriptive statistics were used to describe all variables collected. A multivariable logistic regression analysis was used to determine the predictability of identified risk factors on IC. The predictability of the model was quantified using a nomogram which sums the odds of experiencing IC based on the presence of selected predictors. The sum is correlated to a linear predictor which corresponds to the log odds of experiencing IC. The exponential on the log odds gives the predicted probability of IC.

Results
Three hundred eighteen patients that received at least one dose of micafungin during the time frame for proven or suspected IC were included. IC was confirmed in 105 patients (33%) with endovascular source being the most common (56.2%). The most common Candida species isolated was C. albicans (47.6%). Independent risk factors for development of IC included anti-anaerobic antimicrobial therapy (adjusted odds ratio [aOR], 0.4611; 95% confidence interval [CI], 0.232, 0.914), parenteral nutrition (aOR, 2.115; 95% CI, 1.019, 4.388), and critical illness (aOR, 0.511; 95% CI, 0.315, 0.829). Patients with prediction scores of greater than 50 had an estimated probability of IC greater than 20%.

Conclusion
A prediction score can be a useful tool to estimate the patient-specific risk of IC development. Integration of a risk score for IC into clinical workflow may improve empiric antifungal prescribing and reduce echinocandin utilization.

Disclosures
All Authors: No reported disclosures.
905. Impact of a Real-Time Electronic Alert on Antibiotic Treatment Duration for Pneumonia in Hospitalized Patients
Authors: Degnan Kathleen , Saw Steve , Lee Tiffany , Athans Vasilios , Patel Sonal , Binkley Shawn , Uzoma Joy , Hamilton Keith W , Do David , Dutcher Lauren 
Published: December 2022

Abstract

Background
Limiting antibiotic prescribing to the shortest effective duration reduces antibiotic-associated adverse events and resistance. Up to two-thirds of patients receive excessive durations of therapy for pneumonia. This study evaluated the effect of a stewardship intervention to reduce excess antibiotic duration for inpatients with pneumonia.

Methods
A dashboard was developed to generate real-time alerts when inpatients at an academic medical center received antibiotics with an indication of community- or hospital-acquired pneumonia for more than 5 or 7 days, respectively. From November 2019 through April 2021, alerts were regularly reviewed by the antibiotic stewardship (AS) team and intervened upon when patients exceeded the guideline recommended duration of therapy for pneumonia without additional indications for continuing antibiotics. We compared inappropriate duration of therapy pre- and post-implementation of the dashboard by calculating the mean number of excess days of antibiotics beyond the recommended duration. Patients with SARS-CoV-2 infection and patients on hospital services that care for patients with cystic fibrosis, bronchiectasis, or immunocompromising conditions were excluded. Four other hospitals within the same health system that did not utilize the dashboard generated alerts served as a comparison group.

Results
During the intervention period, the AS team reviewed 834 patients with dashboard alerts and documented 115 interventions. For alerts reviewed without intervention, reasons for lack of intervention included active Infectious Diseases consult, additional infection diagnosis requiring a longer duration, and delayed clinical improvement. In the post-implementation period there was a mean of 1.28 excess days of antibiotics for pneumonia compared to the pre-implementation mean of 1.36 excess days. In comparison, aggregating data from the hospitals not utilizing the dashboard, there was a mean of 0.67 excess days post-intervention, compared to a mean 0.62 days pre-intervention.

Conclusion
The pneumonia dashboard is a potentially valuable stewardship tool which may reduce excess days of antibiotics for pneumonia. The dashboard’s impact may be improved by daily review and excluding patients with additional infection diagnoses.

Disclosures
Kathleen Degnan, MD, Gilead: Grant/Research Support.