bluuebunny/crossref_metadata_2025 huggingface dataset:
516. Delivery Mode and Intrapartum Antibiotics Affect the Gut Mycobiome in Newborn Infants and Young Children
Authors: Turunen Jenni , Paalanne Niko , Reunanen Justus , Tapiainen Terhi , Tejesvi Mysore V
Published: December 2022

Background

The gut mycobiome may have important effects on health. Yet, there is limited data on the mycobiome. Previously, we have shown that antibiotic exposure at birth markedly alters the gut bacteriome in children. As fungi and bacteria may have important interactions in the gut microbiome, we hypothesized that perinatal antibiotics may influence the composition of the gut mycobiome.

Methods

For the study, 434 fecal samples were collected at birth, 6 months, and 18 months of age. We extracted DNA from samples using DNeasy PowerSoil Pro kit. We sequenced the ITS2 gene and analyzed the results using QIIME2. The taxonomy was assigned using UNITE database.

Results

At birth, newborn infants had a low-biomass gut mycobiome, which developed over time until the age of 18 months. At the genus level, there was a transition from Candida to Trichosporon and Saccharomyces at 6 and 18 months respectively. Unidentified fungi were found in greater numbers in 18-month stool samples than in earlier samples. Alpha and beta diversity analyses showed statistically significant differences depending on the age of infants.

Both delivery mode and intrapartum antibiotics were associated with significant differences in the gut mycobiome composition. Infants born vaginally had mycobiome with abundant Candida at birth and their mycobiome progressed towards composition dominated by Trichosporon and Saccharomyces. Samples from infants born via C-section had more Malassezia, Hyalotiella and Saccharomyces.

Vaginally delivered infants exposed to antibiotics at birth had more Candida sp. in the gut mycobiome than those unexposed to antibiotics. By 18 months of age, half of the fungi in no intrapartum antibiotic group were unidentified fungi, but more than half of the fungi in the intrapartum antibiotic group were of genus Trichosporon.Figure 1.Taxonomic figures of each sample type. Taxa have been drawn from phylum (innermost level) to species (outermost level).

Figure 2. Taxonomic figures of each sample type are based on the delivery mode. Taxa have been drawn from phylum (innermost level) to species (outermost level).

Figure 3. Taxonomic figures of each vaginal delivery sample are based on the usage of intrapartum antibiotics. Taxa have been drawn from phylum (innermost level) to species (outermost level).

Conclusion

In this prospective cohort study, the gut mycobiome composition of newborn infants and young children was markedly influenced both by delivery mode and exposure to antibiotics at birth. The effects were observed from birth until 18 months of age.

Disclosures

All Authors: No reported disclosures.
523. A Rapid, Objective Measure of the Host Response May Help Guide Efficient and Judicious ED Care for Sepsis
Authors: O’Neal Hollis R , Sheybani Roya , Tse Henry T , Shah Ajay M , Thomas Christopher B
Published: December 2022

Background

Most cases of sepsis present to Emergency Departments (ED’s). Current guidelines stress ED clinicians to intervene before adequate, objective diagnostic and prognostic data are available, resulting in a ‘one size fits all’ strategy. This causes excessive use of broad-spectrum antibiotics and limited resources. The IntelliSep test is an investigational, in vitro host response test that quantifies the state of immune activation by measuring the biophysical properties of leukocytes. The test is performed on EDTA-anticoagulated blood and results in under 10 minutes. The result, the Intellisep Index (ISI), ranges 0.1-10.0, stratified into three interpretation bands of increasing disease severity risk: Green, Yellow, and Red.

This study assesses the Intellisep Index (ISI) as a potential aid for risk stratification and resource allocation for the treatment of patients presenting to the emergency department with possible sepsis.

Methods

Adult patients presenting to the ED with signs or suspicion of infection were prospectively enrolled at multiple US sites (Apr. – Sept. 2019). Patients were followed by retrospective chart review for outcome information and Sepsis-3 adjudication. Treating clinicians were blinded to ISI results.

Results

290 study patients (sepsis prevalence 17.5%) were stratified by the ISI as 160 (55%) Green, 70 (24%) Yellow, and 60 (21%) Red. The diagnostic odds ratio for sepsis was 20.5 (8.2 - 36.0, 95% CI) between the Red and Green Bands. Subjects in the Green Band had significantly lower mortality (p < .01) and severity of illness, as measured by APACHE II (p < .01), SOFA (p < .001), ICU admission (p < .001) and hospital length of stay among survivors (p < .001). However, 16 (10%) subjects in the Green Band received antipseudomonal and / or anti-MRSA antibiotics in the ED; only two of these subjects were septic (both survived without needing ICU care with 0 and 6-day hospital stays). Conversely, 12 septic subjects in the Red Band did not receive broad-spectrum anti-MRSA antibiotics in the ED, with an average hospital length of stay of 8 days and one fatality.

Conclusion

The ISI, a rapid, quantitative measure of immune activation, may offer ED clinicians an aid for rapid risk stratification of patients presenting with suspicion of infection and guide appropriate treatment.

Disclosures

Roya Sheybani, PhD, Cytovale: Employee|Cytovale: Stocks/Bonds Henry T. Tse, PhD, Cytovale: Stocks/Bonds Ajay M. Shah, PhD, Cytovale Inc: Board Member|Cytovale Inc: Ownership Interest|Cytovale Inc: Stocks/Bonds.
537. First Week Post-Operative C-Reactive Protein Kinetics Show Different Patterns of Association with Infection Depending on the Type of Surgery
Authors: van Boekel Anna M , van der meijden Siri L , Geerts Bart F , Arbous Sesmu M , de Boer Mark G
Published: December 2022

Background

C-reactive protein (CRP) is a nonspecific marker of inflammation and due to surgery alone CRP levels are increased post-operatively. Although multiple studies investigated the potential of post-operative CRP levels to predict post-operative infection, its discriminative capacity remained unclear. We aimed to describe the kinetics of CRP for post-operative patients with- and without a post-operative infection for different types of surgery in the first seven post-operative days.

Methods

We conducted a single center cohort study in adult patients undergoing surgery between 2011 and 2021 with the use of whole digital case file extraction (big data). All patients that had either an infectious complication registered, non-prophylactic antibiotics prescribed and/or an infection related surgical re-intervention within 7 days after having undergone surgery, were labelled as having an infection. We analyzed the CRP kinetics in the first seven post-operative days for all these patients.

Results

A total of 39.985 individual patients were included of which 12.002 patients had at least one CRP measurement and 4.014 patients had an infection in the first seven post-operative days. CRP was measured in 66% of the patients with an infection and in 26% of the patients without an infection. In all patients CRP increased during the first two post-operative days regardless of infection status (Figure 1). In cardiothoracic, orthopedic, ear-nose-throat, general and urological surgery CRP decreased after day 2 or 3 in all patients but the absolute CRP value remained higher in the following days in patients with an infection compared to patients without an infection. In gynecological and oral surgery CRP decreased on day 3 in patients without an infection but not before day 4 in patients with an infection. CRP was not discriminative in neurosurgical or plastic surgery patients (Figure 2).

CRP kinetics in the first seven post-operative days for patients with- and without an infection

CRP kinetics for different subspecialties in the first seven post-operative days

CTS = cardiothoracic surgery; ENT = ear-nose-throat surgery; GEN = general surgery; GYN = gynecological surgery; NEUR = neurosurgery; ORAL = oral surgery; ORT = orthopedic surgery; PLA = plastic surgery; URO = urological surgery.

Conclusion

In the first 2 post-operative days CRP increases in both patients with- and without an infection which is probably due to the surgical procedure itself. After the second post-operative day differences in CRP kinetics develop between patients with- and without an infection, but how they differ depends, among other factors, on the type of surgery.

Disclosures

Siri L. van der meijden, MSc, Healthplus.ai: Employee Bart F. Geerts, MD. PhD., Healthplus.ai: Board Member.
538. Human neutrophil gelatinase-associated protein (N-gal) and proinflammatory cytokines as biomarkers of disease severity in children with Hemolyitic Uremic Syndrom (HUS) and Shigatoxin-producing E.coli (STEC) infection.
Authors: Toledano Analía , Caratozzolo Ana , Lanfranchi Romina , Martinez Mayra , Chacoff Marian , Talarico Laura , Contrini María M , Lopez Eduardo Luis
Published: December 2022

Background

Hemolytic Uremic Syndrome (HUS) is a complication of Shigatoxin-producing E.coli (STEC) infection which presents a characteristic triad of microangiopathic hemolytic anemia, thrombocytopenia, and acute renal failure. Preliminary in vitro and experimental animal studies demonstrated that Shigatoxins (STXs) induce the secretion of proinflammatory cytokines. Human neutrophil gelatinase-associated protein (N-gal) has been reported as a marker of acute kidney injury. Dosing serum levels of IL-8, TNF-α, IL-6, IL-1β and N-gal in children with STEC-associated infection and HUS would allow to establish the role of these cytokines as biomarkers of renal injury and severity

Methods

Prospective study during 2017 – 2020 was performed; three groups of patients < 18 years were included: bloody diarrhea (BD), HUS requiring dialysis (HUSD) and HUS and no dialysis requirement (HUSND), all of them with presence of STX in stool. Blood samples were collected at diagnosis (t1) and at 7 days (t2). An immunoassay was used for detection of TNF-α, IL-1β, IL-6, and IL-8 (Bio-Plex Pro Human®, BioRad). An immunoassay (Anti-Lipocalin-2) was used for N-gal detection

Results

Forty-nine children were admitted; 22 (49%) were male. Median age was 24 (IQR 13-36) months. Fourteen patients with BD, 24 patients with HUS: 12 HUSD and 12 HUSND. Eleven healthy children (HC) were included. At diagnosis, higher IL-8 values were found in HUSD vs. BD (p=0.0004), HUSND (0.003) and HC (p= 0.0043). Higher TNF-α values were detected in HUSD vs. BD (P= 0.0001), HUSND (p= 0.0011) and HC (p= 0.0002). Higher TNF-α values were found in patients with BD vs HC (p= 0.0055). HUSD exhibited higher IL-6 values as compared with BD (p= 0.0145) and HC (0.0106). N-gal concentrations were higher in HUSD vs. BD (P= 0.0120), HUSND (P= 0.0166) and HC (p= 0.0049). A decrease in IL-8 was observed in HUSD between t1 and t2 (p=0.0357). (Figure 1)

Conclusion

Interleukin 8, IL-6, and N-gal may be considered as potential serological markers of renal damage and dialysis requirement. TNF-α concentrations are already increased in BD without HUS complications

Disclosures

All Authors: No reported disclosures.
547. Risk factors that can predict adrenal insufficiency in fever of unknown origin
Authors: Go Ji Won , Lee Seung Eun , Park Jung Hwan , Pai Hyunjoo , Kim Dong Sun , Kim Bongyoung
Published: December 2022

Background

Adrenal insufficiency is one of the causes of fever of unknown origin (FUO), however, it is often mistaken for an infectious disease, leading to unnecessary antibiotic use. The purpose of this study is to find out risk factors that can predict adrenal insufficiency in FUO patients so that set a target to recommend the adrenocorticotropic hormone (ACTH) stimulation test.

Methods

This study was conducted retrospectively in a tertiary hospital with 846 beds in South Korea. All adult inpatients (age ≥ 19 years) who have requested a consult with the department of infectious disease (ID) for FUO between 1 July, 2019 and 30 June, 2020 were included in the study. Among them, those who underwent an ACTH stimulation test and had a fever of 37.8°C or higher within 48 hours of the ACTH stimulation test were finally included in the study subjects.

Results

A total of 202 FUO patients were enrolled and 61 (30.1%) were finally diagnosed with adrenal insufficiency. Patient with adrenal insufficiency had higher charlson comorbidity index score than others (2.36±1.88 vs. 1.85±2.06, P=0.016). In addition, higher proportion of patients who used immunosuppressant (31.1% vs. 6.4%, P< 0.001) and/or corticosteroid (19.7% vs. 3.5%, P< 0.001) within 3 months were observed in adrenal insufficiency group. Patients with adrenal insufficiency tended to show hypotension (21.3% vs. 10.6%, P=0.044), lower white blood cell count [10^3/uL] (9.27±6.30 vs. 10.54±5.82, P=0.025), lower hemoglobin (4.38±9.96 vs. 1.70±2.10, P=0.023), lower albumin (8.25±0.94 vs. 8.49±0.60, P=0.009), and higher creatinine (1.39±1.61 vs. 1.05±1.57, P=0.044) than those without adrenal insufficiency. In a multivariate analysis, use of immunosuppressant within 3 months (OR 6.06, 95% CI 1.82–20.13, P = 0.003), use of corticosteroid within 3 months (OR 8.23, 95% CI 1.35–50.17, P = 0.022), sodium ≥ 136.7 (OR 3.43, 95% CI 1.49–7.88, P = 0.004), and calcium ≥ 8.4 (OR 0.31, 95% CI 0.14-0.71, P = 0.005) were proven to be factors that can predict adrenal insufficiency in FUO patients.

Conclusion

When FUO patients have a history of immunosuppressant/corticosteroid use within 3 months, and/or shows sodium ≥ 136.7, or calcium < 8.4 at initial laboratory test, performing ACTH stimulation test is recommended.

Disclosures

All Authors: No reported disclosures.
589. Clinical Outcomes of Twice versus Thrice daily Metronidazole Dosing for Bacteroides Bloodstream Infections
Authors: Shah Sunish , Adams Kathleen , Topal Jeffrey E , McManus Dayna , Clarke Lloyd , Nguyen Minh-Hong , Shields Ryan K
Published: December 2022

Background

The optimal metronidazole dose for the treatment of Bacteroides spp. has not been defined. The purpose of this study was to evaluate the utility of a twice (BID), rather than thrice (TID) daily metronidazole dosing strategy among patients with bacteremia due to Bacteroides spp.

Methods

Adult, hospitalized patients with bacteremia secondary to Bacteroides spp. between October 2010 and June 2021 were assessed across 11 hospitals. The primary endpoint was clinical failure which was a composite of all-cause 30-day mortality, escalation of antimicrobial therapy, 30-day readmission or recurrence due to an anaerobic infection, positive repeat blood cultures for Bacteroides spp., or failure to resolve leukocytosis or fever.

Results

208 patients were included; 68 received metronidazole 500mg BID and 140 patients received metronidazole 500mg TID (Figure). Patient age, Charlson comorbidity index, and Pitt Bacteremia score were similar among patients receiving BID vs TID dosing (Table 1). On balance, patients who received BID dosing were more likely to receive oral metronidazole and had shorter lengths of hospitalization prior to bacteremia. Overall, there was no significant difference between rates of clinical failure or other outcomes between patients who received BID versus TID metronidazole dosing (Table 2). In the multivariate model, neither the use of TID dosing (OR = 0.74; 95% CI = 0.33–1.65; P=0.457), time to treatment initiation (OR = 1; 95% CI = 0.81–1.22; P=0.968), days of initial non-metronidazole anaerobic therapy (OR = 0.91; 95% CI = 0.59–1.34; P=0.646), pre-infection length of stay (OR = 1.02; 95% CI = 0.99–1.05; P=0.106), admission prior to 2016 (OR = 1.09; 95% CI = 0.49–2.39; P=0.829), or initial oral metronidazole use (OR = 0.45; 95% CI = 0.18–1.03; P=0.066) were significantly associated with clinical failure. Figure 1:Inclusion and exclusion

Non-metronidazole anaerobic coverage consisted of a beta-lactam/beta-lactamase inhibitor, cefoxitin, or a carbapenem Table 1:Demographics and baseline characteristicsTable 2:Clinical outcomes*Patients were considered to have escalated antimicrobial therapy if, in the setting of ongoing signs of infections, antimicrobial therapy was either broadened or the frequency of metronidazole was increased from twice daily to thrice daily.

Conclusion

In the largest study to date of patients with Bacteroides spp. bacteremia treated with metronidazole, there was no significant difference between BID and TID metronidazole dosing strategies. In the absence of a clear benefit, metronidazole 500mg BID is a reasonable dosing strategy in lieu 500mg TID for infections due to Bacteroides spp.

Disclosures

Ryan K. Shields, PharmD, MS, Infectious Disease Connect: Advisor/Consultant|Merck: Advisor/Consultant|Merck: Grant/Research Support|Roche: Grant/Research Support.
601. Characterizing Modifiable Risk Factors for Liposomal Amphotericin B (L-AMB) Nephrotoxicity
Authors: Bialick Kate , Leu Teresa , Liu Catherine , Tverdek Frank P
Published: December 2022

Background

Liposomal amphotericin B (L-AMB) is a broad spectrum anti-fungal utilized in the treatment of serious fungal infections. Despite its liposomal formulation aimed at reducing toxicity, it is still associated with relatively high rates of nephrotoxicity. Few studies have attempted to assess the effectiveness of mitigation strategies to lower the risk of L-AMB-associated nephrotoxicity.

Methods

The purpose of this study is to characterize the time course of nephrotoxicity secondary to L-AMB, evaluate modifiable risk factors for L-AMB-related nephrotoxicity, and identify potential interventions to minimize nephrotoxicity. A retrospective chart review of inpatients who received L-AMB: Oct 1, 2020 through Jan 31, 2022 at the University of Washington Medical Center (UWMC) and Seattle Cancer Care Alliance (SCCA). The primary objective was to identify the incidence and onset of L-AMB related nephrotoxicity. Eligible patients ≥18 years old with a history of hematologic malignancy, solid organ transplant, or bone marrow transplant were included. Univariable associations were evaluated with either Chi-square or T-test.

Results

A total of 132 patients were reviewed with 77 patient courses included. The baseline characteristics are depicted in TABLE 1. The mean dose of L-AMB was 4.9 mg/kg with an average treatment duration of 8.2 days. Nephrotoxicity occurred in 33.8 % of patients with median onset of 3 days. IV hydration occurred in 88.5 and 68% of patients pre and post, respectively. Patients had at least one concomitant nephrotoxin (87 %) with an average of 2. Comparing those patients with nephrotoxicity and those without, age and L-AMB duration, were associated with nephrotoxicity. Table 1- Baseline CharacteristicsTable 2- Nephrotoxicity Risk Factors

Conclusion

L-AMB nephrotoxicity occurred at a relatively high rate in this patient population despite high utilization of toxicity mitigating strategies such as IV hydration. Nephrotoxicity was associated with longer durations of therapy. Further investigation is necessary to determine alternative strategies for nephrotoxicity prevention.

Disclosures

All Authors: No reported disclosures.
603. Comparing assays for Clinical Phage Microbiology in biofilm
Authors: Rimon Amit , Coppenhagen Shunit , Nir-Paz Ran , Hazan Ronen
Published: December 2022

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

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

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 > 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>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) > 50mL/min in 71.4% of patients (n = 10), CrCl 30-50 mL/min in 28.5% (n = 4), and < 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 > MIC for penicillins, 60%fT > MIC for cephalosporins, 40%fT > MIC for carbapenems) was achieved in 100% (n=14) of patients. Dose adjustment was not needed in all 14 cases. However, 100%fT > 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 >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

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 > 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

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

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

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 > 16 mg/L) and aztreonam alone (MIC > 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

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

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.
912. Impact of Rapid Identification and Stewardship Intervention on Coagulase-negative Staphylococcus Bloodstream Infection (BSI)
Authors: Goshorn Eli S , Viehman Alex , Ryan Bariola J , Khadem Tina , Potoski Brian , Shields Ryan K
Published: December 2022

Background

Coagulase-negative staphylococci (CoNS) are commonly isolated from blood cultures (BCx). Most do not require treatment (tx), yet antibiotics are frequently initiated. Workup of CoNS BSI consumes significant resources. We aimed to demonstrate the safety and efficacy of an early algorithm-based rapid diagnostic testing (RDT) plus antimicrobial stewardship (ASP) intervention.

Methods

BCx with CoNS were captured in 3 time periods to represent pre-RDT, RDT-only, and RDT+ASP. GenMark ePlex RDT was implemented for all Gram-positive BCx, identifying S. epidermidis and other non-aureus/lugdunensis Staphylococcal species. Results were called to ASP in both RDT-only and RDT+ASP periods. In the latter, a prospective algorithm was implemented to standardize ASP recommendations (Fig 1) for cases classified as simple, uncomplicated, and complicated BSI. The primary outcome was receipt of < 24h of antibiotic tx. Safety outcomes included rates of recurrent BSI and hospital readmission.

Results

184 patients were included (Fig 2). The median age was 62, 54% were male, and the median Charlson comorbidity index was 5. 41% had a central venous catheter at time of BSI. Overall, 67%, 19%, and 12% of cases were classified as simple, uncomplicated, or complicated BSI, respectively (Fig 3). BSI class and patient demographics did not vary between periods. During pre- and post-RDT periods, median days of antibiotic tx did not vary significantly for patients with simple BSI (1.1 vs 1.2). In contrast, median days of tx were reduced to 0 (P=0.005) for simple BSI in the RDT+ASP period. Overall, 54% of patients with CoNS BSI received < 24h of tx in RDT+ASP time period compared to 34% (P=0.009) in the combined pre-RDT and RDT-only periods. Tx was entirely avoided in 28% of CoNS BSI cases in the RDT+ASP period compared to 16.5% of cases in other periods (P=0.07). 7 cases classified as simple were reclassified as uncomplicated or complicated after further work up. Rates of recurrent BSI and 30-day readmission were comparable across time periods.

Conclusion

Our algorithm-based ASP + RDT intervention reduced antibiotic tx for CoNS BSI, an effect not realized with RDT alone. These data attest to the safety and efficacy of early ASP intervention for patients with CoNS BSI identified by RDTs at the time of positive BCx.

Disclosures

J Ryan Bariola, MD, Infectious Disease Connect: Salary support|Merck: Grant/Research Support Tina Khadem, PharmD, Infectious Disease Connect: Salary support|Merck: Grant/Research Support Brian Potoski, PharmD, BCPS-AQ ID, Merck Group: Grant/Research Support Ryan K. Shields, PharmD, MS, Infectious Disease Connect: Advisor/Consultant|Merck: Advisor/Consultant|Merck: Grant/Research Support|Roche: Grant/Research Support.
922. Promotion of antimicrobial stewardship after issuing antimicrobial resistance national action plan in Japan: a systematic review of the literature from 2016 to 2020
Authors: Honda Hitoshi , Takamatsu Akane
Published: December 2022

Background

Antimicrobial resistance (AMR) is a global threat, potentially causing a significant healthcare burden. In 2016, the Japanese government issued the national action plan for AMR. Since the issuance of the Japanese AMR action plan in 2016, several ASP studies have been published in Japanese institutions. We, therefore, performed a systematic review of the literature on ASP studies conducted in Japanese institutions to elucidate the current ASP activities and understand the impact of the AMR action plan on the current state of ASPs in Japan.

Methods

We searched literature based on two databases, including Medline (PubMed) and EMBASE, from January 2016 through September 2021. The risk of bias for interventional studies was assessed using ROBINS-I, and Newcastle-Ottawa Scale was used to determine the quality of cohort studies, case-control studies, and cross-sectional studies.

Results

We identified 80 studies subsequently included in the systematic review. The proportions of each type of studies were following: 30 (37.5 %) interventional studies, 15 (18.8 %) database-oriented studies, 9 (11.3 %) analytical studies (1 case-control study, 6 cohort studies, and 2 cross-sectional studies), 12 (15.0%) descriptive studies (3 cohort studies, and 9 cross-sectional study). All interventional studies were a before-after trial and interrupted time series analysis for assessing the changes in antimicrobial consumption by interventions. The subsequent targeted or overall antimicrobial use has significantly decreased (changes in a proportion ranging from 19.0 to 99.4 % in oral agents and 33.0 to 76.2 % in intravenous agents). In database-oriented studies, five studies demonstrated decreasing antimicrobial consumption after issuing AMR national action plan.

Conclusion

The present systematic review revealed that increasing numbers of ASP studies were published after issuing the AMR action plan and showed the promotion of successful interventions of ASP studies. A few database-oriented studies showed a positive impact of AMR action plan on antimicrobial activity consumption. However, further development of high-quality studies, especially interventional studies using appropriate methodology and standardized data collection, is continuously needed.

Disclosures

All Authors: No reported disclosures.