bluuebunny/crossref_metadata_2025 huggingface dataset:
574. Antibodies Targeting Candida albicans Als3 and Hyr1 Antigens Protect Neonatal Mice from Candidiasis
Authors: Singh Shakti , Nabeela Sunna , Barbarino Ashley M , Ibrahim Ashraf S , Uppuliri Priya
Published: December 2022

Background

Pre-term infants in neonatal intensive care units are vulnerable to fungal sepsis. In this patient population, C. albicans remains the predominant fungal pathogen causing high morbidity and mortality, despite antifungal therapy. Thus, new therapeutic strategies against neonatal candidiasis are needed. We have reported that vaccination with C. albicans cell wall N-termini recombinant proteins Als3 (rAls3p-N) and Hyr1 (rHyr1p-N) protected adult mice from disseminated candidiasis. Further, NDV-3A (rAls3p-N+alum) protected women from recurrent vulvovaginal candidiasis, which was correlated with anti-Als3p IgG2 isotype titer. Here, we evaluated the efficacy of Als3p and Hyr1p based vaccine in a neonatal candidiasis mouse model.

Methods

Inbred BALB/c mice strain was used for both active and passive vaccination studies. Female 4-6 weeks old mice were vaccinated with rAls3p-N or rHyr1p-N antigens mixed with complete Freund’s adjuvant (CFA, priming)/incomplete Freund’s adjuvant (IFA, boosting). Mice were mated after the boost and pups (3 days old) born to vaccinated mice were infected intraperitoneally (IP) with C. albicans. For passive vaccination, 3 days old naive pups were IP infected with C. albicans and treated with serum obtained from vaccinated adult mice. Fungal burdens were determined in the kidneys of infected neonate mice at 3 days post-infection. Antibody titers were determined by ELISA.

Results

CFA/IFA formulated Als3 and Hyr1 vaccines induced a robust antibody response with a ten-fold higher titer of IgG2, than attained by either antigen formulated with alum. Transplacental transfer of these antibodies significantly reduced the fungal burden in the kidneys of mice pups, and adoptive transfer of vaccinated mothers’ sera into pups displayed similar levels of protection. Neutrophils were found important for this efficacy. Anti-Hyr1 antisera potentiated the activity of fluconazole in protecting from C. albicans infection.

Conclusion

Our current studies are the first to emphasize the importance of anti-Als3 and anti-Hyr1 antibodies in preventing neonatal candidiasis. Considering that Candida infections in low birth weight infants is a lethal infection, active and passive vaccination strategies using these antigens could have profound clinical significance.

Disclosures

All Authors: No reported disclosures.
610. Low Rates of Acute Kidney Injury (AKI) in Outpatient Vancomycin Managed by Pharmacists using Precision Dosing Software
Authors: Schroeder Claudia P , Couch Kimberly A , Gee Joyce F , Van Anglen Lucinda J
Published: December 2022

Background

AKI is a complication of intravenous vancomycin (VAN) occurring in up to 43% of patients (pts) during hospitalization. Data on AKI in pts receiving VAN through outpatient parenteral antimicrobial therapy (OPAT) are limited. There is suggestion that VAN managed through precision dosing pharmacokinetic (PK) software may limit this occurrence. We evaluated the AKI rate of pts receiving VAN as OPAT through Physician Office Infusion Centers (POICs) over a 12-month period.

Methods

A review was conducted of OPAT VAN pts treated in 2021 with therapeutic drug monitoring (TDM) performed (InsightRX) and ≥2 VAN serum levels. These pts were then evaluated for AKI, defined as increase in serum creatinine (SCr) ≥1.5 times baseline. Pts on dialysis were excluded. Data included comorbidities, diagnosis, VAN regimen, concomitant medications, SCr, and VAN serum levels. PK parameters were collected with trough values and estimated 24-hr area under the curve (AUC24). Outcome of therapy was assessed following identification of AKI.

Results

A total of 330 pts from 51 POICs had TDM performed. Of these, 27 (8.2%) developed AKI. Median age was 61 years, 67% were male, and baseline SCr was 0.8 mg/dL (IQR, 0.7-1.0). Most pts (89%) were on concomitant nephrotoxic medications. Median duration of OPAT was 34 days (IQR, 18-41) with onset of AKI after 16 days (IQR, 10-21). At time of AKI, the median SCr increase was 1.7 times baseline (IQR, 1.5-2.0) with a corresponding VAN trough of 21 mg/mL (IQR, 15-28) and AUC24 of 572 mg*h/L (IQR, 495-660). As a result, VAN was discontinued in 14 (52%), dose or frequency modified in 10 (37%) with completion of VAN, and no modifications performed in 3 (11%). One pt who discontinued VAN required hospitalization due to AKI with resolution.

Conclusion

VAN managed by pharmacists in an OPAT setting using precision dosing software resulted in a low rate of AKI. Median rise in SCr was < 2 times baseline for those with AKI. Rapid identification of early AKI by the pharmacist resulted in changes to the regimen or VAN discontinuation, preventing serious patient sequelae. This supports the need for pharmacist-led monitoring in an outpatient setting with long VAN therapy durations.

Disclosures

Lucinda J. Van Anglen, PharmD, Merck & Co.: Grant/Research Support|Paratek: Grant/Research Support.
615. Pharmacodynamics (PD) of the Beta-Lactamase Inhibitor Xeruborbactam When Administered in Combination with Meropenem
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. The purpose of these studies was to determine the pharmacodynamic parameter that best described the activity of XERU against Enterobacterales and A. baumannii when administered in combination with a fixed dosage regimen of meropenem in the neutropenic mouse thigh infection model.

24h Free Xeruborbactam AUC vs CRE

24h Free Xeruborbactam AUC vs CRAB

Methods

Seven carbapenem resistant Enterobacterales (CRE) and six carbapenem-resistant A. baumannii (CRAB) isolates were used in these studies. Mice were rendered neutropenic, infected with ∼107 CFU/thigh and were treated with various doses of XERU in combination with meropenem (300 mg/kg q2h) by the IP route starting 2 hours post infection for 24 hours. The meropenem dosage regimen was fixed and designed to simulate 2 g every 8 hours by 3-hour infusion in humans. Plasma exposures (PK) were measured in neutropenic, infected mice. The relationship between XERU PK-PD indices and the reduction in the log number of CFU per thigh were analyzed by using the sigmoid Emax PD model.

Results

The activity of XERU was best described by the % 24h free XERU plasma concentrations exceeded 1 mg/L and 24h free xeru plasma AUC.

Xeru PK-PD Parameters in Combination with Meropenem against CRE

Xeru PK-PD Parameters in Combination with Meropenem against CRAB

Conclusion

The PK-PD of XERU was best described by the % 24h free XERU plasma concentrations exceeded 1 mg/L and 24h free XERU plasma AUC. The PK-PD of XERU in combination with meropenem and the clinical PK of both drugs support further clinical development for the treatment of carbapenem-resistant isolates of Enterobacterales and A. baumannii.

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.
618. Pharmacokinetic/pharmacodynamic analysis of combination therapy with continuous infusion (CI) fosfomycin plus extended-infusion (EI) or CI beta-lactams for treating documented carbapenem-resistant Gram-negative bloodstream infections and/or hospital-acquired pneumonia: a case series
Authors: Gatti Milo , Rinaldi Matteo , Cojutti Pier Giorgio , Horna Clara Solera , Fornaro Giacomo , Viale Pierluigi , Giannella Maddalena , Pea Federico
Published: December 2022

Background

To describe the pharmacokinetic/pharmacodynamic (PK/PD) behaviour and the microbiological outcome of combination therapy with continuous infusion (CI) fosfomycin plus extended-infusion (EI) or CI beta-lactams for treating severe carbapenem-resistant Gram-negative (CR-GN) infections.

Methods

Single-center retrospective study of patients who were treated with CI fosfomycin plus EI or CI beta-lactams for severe CR-GN infections and who underwent therapeutic drug monitoring (TDM), from 01 April 2021 to 31 January 2022. Concentrations of CI fosfomycin, meropenem and ceftazidime-avibactam were determined at steady-state (Css), while those of EI cefiderocol were measured at trough (Cmin). The desired joint PK/PD targets of combination therapy were considered as optimal when simultaneously the area-under-the curve to minimum inhibitory concentration (AUC/MIC) ratio for fosfomycin was > 83 and the Css/MIC for meropenem or for ceftazidime-avibactam or the Cmin/MIC ratio for cefiderocol was > 4 (quasi-optimal if only one of the two was achieved, and suboptimal if none of the two was achieved). Relationship between the joint PK/PD targets and microbiological failure (MF) defined as isolation of the same pathogens from follow-up blood cultures or BAL and assessed within 30 days of treatment onset, was investigated.

Results

Among the 16 retrieved patients with documented CR-GN infections, 12 underwent TDM of both fosfomycin and beta-lactams, and seven out of these (3 HAP, 3 BSI+HAP, and one BSI) had determination of fosfomycin MIC determined by agar-dilution (see Table). The joint PK/PD targets were optimal in 4 cases and quasi-optimal in the other 3y. MF occurred in two patients (29%) who were affected by HAP, received combination therapy with ceftazidime-avibactam, and achieved only quasi-optimal joint PK/PD targets (with fosfomycin AUC/MIC < 83). No MF occurred in patients with optimal joint PK/PD targets.

Summary of the relationship between PK/PD targets and microbiological failure in patients receiving combination therapy with CI fosfomycin plus EI/CI beta-lactams

Conclusion

CI fosfomycin in combination with EI/CI beta-lactams may allow for the achievement of optimal joint PK/PD targets in most patients with CR-GN infections, and may represent a potential strategy for minimizing the risk of MF.

Disclosures

All Authors: No reported disclosures.
627. Too Much of a Good Thing? The Clinical Effects of Very High Serum Posaconazole Levels
Authors: Jensen Kelsey L , Mara Kristin , Jannetto Paul J , Chesdachai Supavit , Yetmar Zachary A , Abu Saleh Omar M , Rivera Christina G
Published: December 2022

Background

Posaconazole therapeutic drug monitoring (TDM) is widely utilized to assess therapeutic efficacy and safety (i.e., hepatotoxicity, QTc prolongation); however, little is known about clinical effects of very high serum posaconazole serum levels (i.e., ≥ 5000 mg/mL). Reported incidence rate of adverse drug reactions (ADRs) with posaconazole per most recent clinical trial was ∼30%. The primary objective was to compare the ADR incidence in patients with serum posaconazole levels of 3000-4999 ng/mL to ≥5000 ng/mL.

Methods

This retrospective cohort study included adult patients with a posaconazole serum level ≥3000 ng/mL from 1/1/2019 to 04/30/2021. The primary outcome was symptomatic ADR at time of first serum level ≥3000 ng/mL. Secondary outcomes were laboratory defined hepatoxicity, electrolyte and adrenal laboratory abnormalities, QTc changes, and dose changes in response to TDM. Patient outcomes were censored after the first serum level and were compared between groups using Fisher’s exact tests.

Results

Ninety patients met inclusion criteria, 80 with a level of 3000-4999 ng/mL and 10 with a level of ≥ 5000 ng/mL occurring at a median of 91 days (26-443) and 27 days (12-45) from posaconazole initiation, respectively. Majority of patients were immunocompromised (55.6% transplant recipients, 28.9% active malignancy, 5.6% other) with a split of treatment (50%) and prophylaxis (42.2%) indication. Symptomatic ADRs were very common in patients with posaconazole levels of ≥5000 ng/mL and 3000-4999 ng/mL (80% vs. 58.8%; p=0.31), primarily neurologic (49.1% overall) followed by gastrointestinal (32.7% overall). Hepatotoxicity was also common (≥5000 ng/mL 40% vs 3000-4999 ng/mL 23.4%, p=0.26). Fifty percent of patients had the posaconazole dose continued without change. Electrolytes and QTc results were similar between groups, but median overall QTc was borderline high (456 [IQR 435, 479]).

Conclusion

There are safety concerns for patients with serum posaconazole levels ≥3000 ng/mL. Posaconazole levels should be monitored and, importantly, dose adjusted according to serum level and patient symptoms for both treatment and prophylaxis indications.

Disclosures

Christina G. Rivera, PharmD, Gilead: Grant/Research Support|Gilead: Honoraria|Insmed: Honoraria.
636. Meningococcal Vaccination and Antibiotic Prophylaxis Practices in Solid Organ Transplant Recipients undergoing Eculizumab Therapy
Authors: Bhaimia Eric , Yetmar Zachary A , Mahmood Maryam , Stacy Bernard , Stephen Jenise , Vikram Holenarasipur R , Brumble Lisa M
Published: December 2022

Background

Eculizumab, an inhibitor of terminal complement activation, has been utilized in pre-transplant desensitization, treatment of antibody-mediated rejection and thrombotic microangiopathy in solid organ transplant recipients (SOTR). Eculizumab is associated with meningococcal disease, leading to guidelines for vaccination against serogroups ACWY (menACWY) and B (menB) at least 2 weeks prior to eculizumab therapy. In persons requiring emergent use of eculizumab, prophylaxis for at least 2 weeks is recommended. SOTRs respond suboptimally to vaccination, raising consideration for pre-transplant vaccination and prolonged prophylaxis in those undergoing eculizumab therapy. We sought to describe meningococcal vaccination and prophylaxis practices among SOTRs receiving eculizumab.

Methods

We performed a retrospective chart review of meningococcal vaccination, including number and timing pre- or post-transplant, along with prophylaxis prescribing and duration in SOTRs receiving eculizumab across 3 distinct Mayo Clinic Enterprise sites (Rochester, Arizona, and Florida).

Results

200 SOTRs receiving at least one dose of eculizumab between 1/1/2008 and 9/16/2021 were reviewed. Eculizumab indications included antibody mediated rejection (38%), desensitization (26%), and thrombotic microangiopathy (19%). 83% (166/200) of SOTRs received eculizumab for an unanticipated post-transplant complication. Vaccination rates were 82% (164/200) and 35.5% (71/200) for menACWY dose 1 and 2, respectively, and 54% (108/200) and 28.5% (57/200) for menB dose 1 and 2, respectively. The majority received their first vaccination post-transplant: menACWY 66.5% (133/200) and menB 2.5% (185/200). Among those without vaccination pre-eculizumab, 22.3% (41/184) were not prescribed prophylaxis. The median duration of prophylaxis was 62 (range 4-2651) days.

Conclusion

Most SOTRs underwent meningococcal vaccinations near the time of eculizumab administration post-transplant for an unanticipated complication. One-fifth of those meeting criteria were not provided meningococcal prophylaxis. These findings may support pre-transplant administration of meningococcal vaccinations and heightened awareness for meningococcal prophylaxis in SOTRs receiving eculizumab.

Disclosures

All Authors: No reported disclosures.
637. Transplant Candidacy for Persons Living with HIV and End-Stage Renal Disease at MUSC
Authors: Crawford Kyle M , Adekunle Ruth O
Published: December 2022

Background

Persons Living with HIV (PLWH) with chronic kidney disease progress to end-stage renal disease (ESRD) at a faster rate than HIV-negative individuals. Unfortunately, there is increasing data to suggest that PLWH are less likely to be waitlisted. We reviewed the transplant care continuum among PLWH at the Medical University of South Carolina (MUSC).

Methods

This was a retrospective review of PLWH and ESRD who either received care at MUSC Health Care System or were referred for Kidney transplant at MUSC between May 1st, 2012 and December 31st, 2021. Cases were included if a PLWH and ESRD had not died before being referred for kidney transplant, had evidence of pursuit of kidney transplant, and sufficient data of their transplant process were available in the medical record system. Descriptive statistics were used to analyze demographic and clinical characteristics as well as the transplant care continuum of PLWH and ESRD at MUSC.

Results

57 PLWH and ESRD were included in the analysis. Of these, 45 (79%) were referred for kidney transplant (Table 1). The median age at the time of referral was 52 (range 26 - 78), 33 (73%) were males and 42 (93%) were of the Black race. The most common causes of ESRD were Multifactorial (36%), HIV-Associated Nephropathy (24%) and unknown (16%). Almost all patients had hypertension (96%) and 29% of patients had diabetes. Additionally, prevalent comorbidities include psychiatric conditions (53%), history of substance use (43%) and history of tobacco use (36%). Of those referred for kidney transplantation, 32 (71%) started a transplant evaluation, 24 (53%) completed the transplant evaluation, 22 (49%) were waitlisted, and 13 (29%) were transplanted. Common reasons why patients did not complete transplant evaluation included not meeting HIV criteria for transplant (9%), having too many comorbidities (9%), and not completing testing (9%).

Clinical Characteristics of the 45 HIV Patients with ESRD Who Were Referred to Kidney Transplant at MUSC

Clinical Data on Transplant Care Continuum, n = 45

Conclusion

The majority of PLWH with ESRD seen at MUSC were referred for kidney transplant and started the evaluation process. More is needed, though, to assist patients in completing the transplant evaluation process and making it to the transplant waitlist, with the ultimate goal of transplantation.

Disclosures

All Authors: No reported disclosures.
653. Characterizing Antibacterial Regimen Modification, Patient Characteristics, and Outcomes for Patients with Complicated Gram-negative Bacterial Infections
Authors: Yamaki Jason , Dillon Ryan J
Published: December 2022

Background

There are few studies describing the rationale or frequency of empiric or directed therapy treatment modification behaviors among patients with complicated Gram-negative bacterial infections (GNBI). We sought to characterize patient and treatment characteristics, details of regimen modification, and patient outcomes.

Methods

This retrospective chart review included patients, admitted from 1/1/2019-12/31/2020 to Hoag Memorial Hospital, with a complicated GNBI due to an extended spectrum cephalosporin resistant pathogen. We present an interim descriptive analysis of 60 patients: demographics, ABX modifications, rationale and timing for modifications, and patient outcomes. ABX modifications were defined a GNB ABX switched, added, or removed.

Results

The predominant culture sources were urine and bloodstream. ESBL organisms (38%) and Pseudomonas spp (32%) were most common. Inpatient initial empiric therapies included TZP (33%), MEM (20%), and CRO (17%). 32% of patients did not have any modifications to their ABX regimens. For patients where modifications occurred this ranged from 0 to 6 changes. Time to the first modification ranged from 2 – 196 hours. For initial modifications, all were considered escalations, and most were based on preliminary culture results (36%), lack of patient response (28%), additional history review (28%) and decompensation (1.7%). No difference in 30 or 90-day mortality or 90-day readmission was observed for patients that did or did not have ABX modifications.

Conclusion

Many patients experience modification to GNB targeted antibacterials, in almost all cases, rationale for change was documented. In this interim analysis no difference in patient outcomes was observed. However, it is well established that increased duration of therapy and exposure to numerous antibacterial agents can increase healthcare resource utilization and may negatively impact local ecology, respectively.

Disclosures

Jason Yamaki, PharmD, PhD, Merck & Co. Inc.,: Grant/Research Support Ryan J. Dillon, MSc, Merck: Employee|Merck: Stocks/Bonds.
655. Combination Eravacycline Therapy for Carbapenem-Resistant Acinetobacter baumannii Pneumonia
Authors: Jackson Melissa N , Ortwine Jessica , Wei Wenjing , Mang Norman S , Prokesch Bonnie C
Published: December 2022

Background

Acinetobacter baumannii typically causes infections in debilitated, hospitalized patients and is difficult to treat due to multiple virulence factors and the presence of intrinsic and acquired antibiotic resistance mechanisms leading to frequent isolation of multi-drug resistant (MDR) phenotypes. Due to problematic pharmacokinetics and/or dose-limiting toxicities of salvage agents, combination therapy with aminoglycosides, ampicillin/sulbactam, polymyxins, minocycline, or tigecycline, is often used. Eravacycline has demonstrated greater in-vitro potency against A. baumannii compared to other tetracycline derivatives making it potentially the more appealing option. However, its utility is hindered by a lack of data supporting pharmacodynamic targets and adequate dosing strategies for CRAB. The goal of this case series was to describe our experience with the use of combination eravacycline therapy for the treatment of CRAB pneumonia.

Methods

This case series included all patients ≥ 18 years of age, diagnosed with SARS-CoV-2, ≥ 1 sputum culture positive for CRAB and a clinical diagnosis of new bacterial pneumonia, who received at least one dose of eravacycline between April 1st and October 1st, 2020. The primary outcome was clinical resolution of CRAB pneumonia. Secondary outcomes evaluated microbiological resolution, need for extended durations of therapy, and frequency of re-starting CRAB therapy within 48 hours of completion.

Results

In total, 25 patients were included in this case series. The median duration of combination therapy was 10 days. Most patients (96%) received eravacycline + ampicillin/sulbactam, with 7 of those patients also receiving inhaled colistin (Table 2). In total, 17 (68%) patients achieved clinical resolution of CRAB pneumonia. Post-treatment sputum cultures were collected in 18 patients, of which 13 (72%) achieved microbiological resolution. One patient received > 14 days of therapy and no patients re-initiated therapy within 48 hours of eravacycline completion. Table 1:Baseline CharacteristicsTable 2:Study Outcomes

Conclusion

In this small case series, eravacycline showed favorable clinical outcomes in patients with CRAB pneumonia. In light of limited treatment options, this agent can be considered for CRAB pneumonia salvage therapy.

Disclosures

All Authors: No reported disclosures.
658. Evaluation of Effectiveness of Cefmetazole vs Meropenem for Invasive Urinary Tract Infections Caused by ESBL-Producing Escherichia coli: A Prospective Multicenter Observational Study
Authors: Hayakawa Kayoko , Uemura Kohei , Matsumura Yasufumi , Sakurai Aki , Tanizaki Ryutaro , Shinohara Koh , Hashimoto Takehiro , Kato Hideaki , Matono Takashi , Hase Ryota , Mawatari Momoko , Hara Hiroshi , Hamada Yukihiro , Saito Sho , Doi Yohei
Published: December 2022

Background

ESBL-producing E. coli (ESBLEC) continues to increase worldwide. For the infection due to ESBLEC, no antimicrobial agent has clearly demonstrated therapeutic effectiveness comparable to that of carbapenem. Overuse of carbapenems may lead to an increase in carbapenem-resistant bacteria. Cefmetazole (CMZ) is active against ESBLEC, however, there are limited multicenter studies on the effectiveness of CMZ, an important carbapenem-sparing therapy for the treatment of ESBLEC.

Methods

This prospective, observational study included patients hospitalized for invasive urinary tract infection (iUTI) due to ESBLEC between March 2020 and November 2021 at 10 centers in Japan, with either CMZ or meropenem (MEM) initiated within 96 hours of culture submission as definitive therapy, and used for at least 4 days. The diagnosis of iUTI was made in patients with a fever of ≥37.5°C, symptom of pyelonephritis such as back pain, pyuria, and ESBLEC detected in urine (≥10^4 CFU/mL). Outcomes included clinical effectiveness (resolution of all clinical symptoms or improvement to pre-infection status) between day 4 to 6 of treatment (early) and between the final day of treatment and 2 days later (late), microbiological effectiveness (reduction to ≤10^3 CFU/ml) between day 4 to 6, and mortality. Outcomes were adjusted for the inverse probability of propensity scores (PS) for receiving CMZ or MEM treatment.

Results

Seventy-seven patients in the CMZ group and 46 in the MEM group were included. In univariate analysis, the CMZ group was older than the MEM group, although the MEM group had higher qSOFA, CRP, more frequent medical device use and concurrent bacteremia at the start of study drugs than the CMZ group (Table). Univariate analysis showed no difference in clinical effectiveness, and 30-day mortality was higher in the MEM group. In all cases with available data (CMZ: n=57, MEM: n=22), both drugs were microbiologically effective. After PS adjustment, clinical effectiveness did not differ between the two groups. The risk of 30-day mortality was lower in CMZ group, whereas the risk of recurrence was similar in both groups.

Conclusion

CMZ is as effective as MEM for the treatment of iUTI, suggesting that it is a promising carbapenem-sparing therapy.

Disclosures

Sho Saito, MD, PhD, DAIICHI SANKYO: Grant/Research Support|EVEC: Grant/Research Support|EVEC: Patents obtained through collaborative research|SHIONOGI: Grant/Research Support|Takeda: Advisor/Consultant.
674. Successful Management of ESBL Infections in Physician Outpatient Infusion Centers (POICs)
Authors: Nathan Ramesh V , Metzger Brian S , Bernett Jorge R , Adams John S , Hengel Richard L , Bhattacharyya Rishi , Schroeder Claudia P , Couch Kimberly A , Van Anglen Lucinda J
Published: December 2022

Background

Infections with extended-spectrum β-lactamase (ESBL)-producing pathogens present treatment challenges with higher costs of care. Hospitalized patients (pts) with ESBL infections often require outpatient antimicrobial therapy (OPAT) following discharge. An Infectious Disease (ID) physician can facilitate optimal management in both the inpatient and outpatient setting, particularly when a POIC is an option. The increase of ESBL incidence led us to evaluate management and outcomes of genitourinary (GU) and intra-abdominal infections (IAI), the top two ESBL diagnoses treated in POICs.

Methods

Records were queried for pts hospitalized with ESBL infection and discharged to a POIC between 2019 and 2020. Primary outcome was completion of OPAT. Non-successful completion was defined as premature discontinuation of OPAT including hospital readmission. Adverse events (AEs) and re-treatment within 30 days were captured.

Results

A total of 112 pts (mean age: 59±17 years, 50% female) from 14 POICs were identified (93 GU, 19 IAI). Of these, 51% had their first ESBL infection and 52% were community-acquired prior to hospitalization. A total of 38% presented with concomitant bacteremia. ESBL E. coli was the predominant Gram-negative pathogen in both infection types (Table 1). Mean hospital LOS was 6±4 days (5±2 days GU, 11±6 days IAI) followed by 13±9 days of OPAT (12±7 days GU, 16±11 days IAI). Carbapenems were most frequently used as treatment (89% ertapenem, 7% meropenem). Overall, 106 pts (95%) successfully completed OPAT. Six pts (5%) discontinued due to hospital readmission. AEs were reported in 15 pts (13%), the majority of which were mild. Re-treatment in the POIC within 30 days post OPAT completion occurred in 6 GU pts. None were lost to follow-up. Table 1 summarizes primary outcome by clinical characteristics. Both GU and IAI pts had 95% successful OPAT completion. Table 1.Successful and non-successful completion of OPAT in patients with ESBL infections

Conclusion

Outpatient treatment of ESBL infections in POICs post-hospitalization showed high completion rates with low occurrence of readmissions and re-treatments. Consistent with a rise in ESBL infections, our incidence of community-acquired ESBL infections prior to hospitalization were high at 52%. Once ESBL infections were identified in the hospital, the ID physicians with a POIC rapidly facilitated discharge to OPAT.

Disclosures

Ramesh V. Nathan, MD, FIDSA, Eli Lilly & Co.: Grant/Research Support Brian S. Metzger, MD, MPH, AbbVie: Advisor/Consultant|Cumberland: Advisor/Consultant Lucinda J. Van Anglen, PharmD, Merck & Co.: Grant/Research Support|Paratek: Grant/Research Support.
676. Synergistic Bacteriostatic and Bactericidal Activity of Fosfomycin Plus Trimethoprim-Sulfamethoxazole Combination Against Carbapenem-Resistant Enterobacteriales, Multidrug-Resistant P. aeruginosa, Carbapenem-Colistin-Resistant A. baumannii, MRSA, and Enterococcus spp.
Authors: Pace John L
Published: December 2022

Background

Fosfomycin (F) inhibits the first committed step of peptidoglycan biosynthesis catalyzed by the MurA enzyme which uses phosphoenolpyruvate as a substrate. Trimethoprim and sulfamethoxazole (TS) inhibit successive steps in folate biosynthesis and are commonly used as a fixed combination (co-trimoxazole). In this study we explored the combination (FTS) of F with TS in several gram-negative and gram-positive bacteria of increasing concern.

Methods

We used the synergy-checkerboard variant of the agar minimal inhibitory concentration (MIC) assay with Mueller-Hinton Agar (glucose-6-phosphate supplemented; CLSI) against a selection of Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa, Acinetobacter baumannii, methicillin-resistant Staphylococcus aureus (MRSA), and Enterococcus spp. clinical isolates to characterize an FTS combination. Component antibiotics, F and TS, and a variety of other antibacterial comparators were evaluated by agar method or broth microdilution. Bactericidal assays of FTS were conducted in broth.

Results

Antibacterial synergy with FTS was exhibited against all E. coli (20/20) at antibacterial concentrations below the individual clinical breakpoints for F and TS. Against K. pneumoniae isolates, all (12/12) that were resistant to F, and many (10/13) resistant to both F and TS, were susceptible to FTS. All P. aeruginosa isolates (18/18) were dually resistant to F and TS. Extrapolating breakpoints for Enterobacteriales, clinically-relevant synergy of FTS was exerted against 11/18 isolates, and susceptibility was achievable for one component in combination against 7/18 isolates. Against A. baumannii, susceptibility values below extrapolated breakpoints for FTS were achieved for most isolates (17/19), and for a few (2/19), susceptibility was observed for one component in combination. FTS was active against all MRSA and Enterococcus spp. regardless of F or TS susceptibility.

Conclusion

The unique synergistic and bactericidal activity of the FTS combination was not impacted by resistance of the tested species to any other antibacterial agent including carbapenem-resistant Enterobacteriales, P. aeruginosa, carbapenem-colistin-resistant A. baumannii, MRSA, or Enterococcus spp.

Disclosures

John L. Pace, PhD, FleurirABX, LLC: Board Member|FleurirABX, LLC: Inventor of company patents|FleurirABX, LLC: Ownership Interest.
895. Comparing Antibiotic Durations in Acute Appendicitis After Source Control
Authors: Alberts John L , Torney Nicholas , Nichols Cynthia
Published: December 2022

Background

Community-acquired acute appendicitis is a common intra-abdominal infection that often requires surgical intervention and antibiotics. Despite guideline recommendations for narrow-spectrum regimens and shorter durations, broad-spectrum agents are frequently used for extended durations in community-acquired cases of appendicitis.

Methods

We conducted a retrospective chart review of 95 adult patients admitted to a community hospital in rural northern Michigan with acute appendicitis with or without perforation who underwent source control and received at least 72 hours of antibiotics after source control. Patients were assigned to a short course group (4-7 days) or a long course group (≥ 8 days). Total antibiotics is the sum of the inpatient duration and outpatient duration after source control. The primary outcome was hospital readmission within 30 days of discharge due to complications related to appendectomy or antibiotic failure. Secondary outcomes included hospital mortality, surgical site infection within 30 days, additional source control needed during initial stay, number of patients receiving piperacillin-tazobactam, and proportion of patients who received guideline concordant duration of therapy.

Baseline characteristics between treatment groups

Results

The primary outcome was met in 1/32 patients (3.13%) from the 4–7 day group and 4/63patients (6.35%) in the ≥8-day group (P = 0.66). There were no cases of mortality. Surgical site infection occurred in 1/63 patients (1.6%) in the ≥8-day group (P = 1). Additional source control was needed in 1/32 patients (3.13%) from the 4-7 day group and 3/63 patients (4.76%) in the ≥ 8 day group (P = 1). Piperacillin-tazobactam was prescribed to 21/32 patients (65.6%) in the 4-7-day group and 42/63 patients (67%) in the ≥ 8day group (P =0.91) Piperacillin-tazobactam was appropriately used in 1/21 patient (4.76%) in the 4-7 day group and 6/42 patients (9.5%) in the ≥ 8 day group (P = 0.41).

Outcomes

Results of the primary outcome and the piperacillin/tazobactam based secondary outcomes

Treatment Duration Between Groups

Comparison of total treatment duration between groups with inpatient and outpatient averages

Total Antibiotic Duration Frequency

Distribution of total antibiotic days of patients analyzed in this study

Conclusion

In patients with community-acquired acute appendicitis with or without perforation who had undergone adequate source control, outcomes were similar between a 4-7 day course of antibiotics and ≥ 8 day course. Piperacillin-tazobactam was often prescribed for community-acquired appendicitis cases despite guideline recommendations.

Disclosures

All Authors: No reported disclosures.
896. Cost-Avoidance Associated with Active Stewardship of Remdesivir
Authors: Dyer April , Locklear Eric , Okoye Obiefuna , Ashley Elizabeth Dodds
Published: December 2022

Background

The COVID pandemic shifted antimicrobial stewardship resources at community hospitals. One reason for this shift was new COVID treatments, the first of which was remdesivir, which received initial emergency use authorization (EUA) for the treatment of COVID-19 in May 2020. The UNC Health Southeastern (UNC SEH) pharmacy director stewarded remdesivir by reviewing patients to ensure they met emergency use authorization (EUA) and guideline-based appropriateness criteria. The infectious diseases physician resolved any disputes regarding patient candidacy for remdesivir. The goal of remdesivir stewardship was to optimize care; however, the shift in workflow presented an unrecognized opportunity for stewards to reduce remdesivir costs.

Methods

The percentage of COVID patient admissions receiving remdesivir at UNC SEH for calendar years 2020 and 2021 was benchmarked against 32 community hospitals in the Duke Antimicrobial Stewardship Outreach Network (DASON) (Figure 1). UNC SEH purchasing data were used to calculate remdesivir expenditures for 2020 and 2021. Next, the anticipated cost if the hospital had prescribed remdesivir to the same percentage of admissions as the DASON mean was calculated. The difference was calculated to determine the cost avoidance achieved by having below average use of remdesivir (Table 1).

Results

At UNC SEH, 28.1% of COVID admissions received remdesivir in 2020 and annual remdesivir expenditures were $693,680. In 2021, 47.45% of COVID-19 admissions received remdesivir and drug expenditures were $1,248,000. The DASON mean % of COVID admissions receiving remdesivir in 2020 was 44.08% and 60.07% in 2021. A total cost avoidance of $726,407 was calculated based on the hospital’s below-benchmark use of remdesivir (Table 1).

Conclusion

UNC SEH achieved significant cost-savings in 2020 and 2021 due to active remdesivir stewardship. The team created a patient-centered model that focused on using drugs for the right patients and the organization realized cost-savings while ensuring that patients received therapy in accordance with remdesivir EUAs and published guidelines.

Disclosures

All Authors: No reported disclosures.
897. Criteria Restricting Inappropriate Meropenem Empiricism (CRIME): A Quasi-Experimental Carbapenem Restriction Pilot at a Large Academic Medical Center
Authors: Wells Drew , Johnson Asia , Lukas Jack , Mason Darius , Cleveland Kerry O , Bissell Aaron , Hobbs Athena L V
Published: December 2022

Background

Carbapenems’ broad spectrum of activity may make these agents appealing for empiric use; however, their use is associated with development of Clostridioides difficile infection (CDI) and multi-drug resistance. Selective use of carbapenems is vital in maintaining their effectiveness. Our study aimed to examine the impact of meropenem restriction criteria on utilization and patient outcomes.

Methods

This single-center, quasi-experimental study was conducted at an academic medical center where an initial medication use analysis found frequent inappropriate meropenem utilization. The antimicrobial stewardship team developed restriction criteria and implemented a pilot in February 2022. Investigators aimed to determine how restriction criteria affected meropenem utilization across 8 weeks in the pre-implementation period compared to the post-implementation period. The primary outcome was to compare the inappropriateness of meropenem utilization. Secondary outcomes included comparison of days of therapy per 1000 patient-days (DOT/1000 PD), hospital length of stay (LOS), frequency of CDI, and acquisition cost.

Results

Across the 8 week timeframes, reductions in inappropriate meropenem use (64.5% vs 12.8%; p< 0.001), duration of therapy (5.8 [3.2-7.3] vs. 2.4 [1.0-5.5] days, p< 0.0001), and utilization (30.5 vs. 8.3 DOT/1000 PD, p=0.04) in the pre- and post-implementation periods, respectively, were observed. Total number of meropenem orders decreased by 65% (p< 0.001). Implementation of restriction criteria also resulted in decreased median hospital LOS between periods (11.9 [7.8-20.4] vs. 9.2 [5.4-15.2] days, p=0.05). There was no difference in frequency of CDI (2 vs. 0, p=0.99). Projected annual cost savings was approximately $57,300.

Conclusion

Implementation of antimicrobial stewardship-initiated restriction criteria can reduce inappropriate utilization of meropenem, overall number of orders, and total duration of therapy.

Disclosures

Kerry O. Cleveland, MD, AbbVie: Honoraria|Cumberland: Honoraria|Merck: Honoraria|Pfizer: Honoraria.
919. Let’s GO PO: Impact of Monthly Feedback on a Longitudinal Intravenous to Oral Antimicrobial Conversion Initiative
Authors: Hayes Jillian E , Carr Amy L
Published: December 2022

Background

Timely conversion of antimicrobials from intravenous (IV) to oral (PO) route has been shown to decrease costs and length of stay (LOS) without compromising safety and efficacy of therapy. Use of oral antimicrobials may additionally prevent complications related to IV catheters, such as infection, emboli, and patient discomfort. An approved IV to PO policy allowed pharmacists to convert orders for fourteen included antimicrobials and eligible patients at time of order verification.

Methods

This single-center, retrospective, comparative study was conducted at AdventHealth Orlando, a 1,368-bed community teaching hospital in central Florida. In November 2020, six clinical pharmacist teams began receiving monthly feedback on IV to PO conversion rates in the form of a RePOrt Card, containing IV to PO conversion rates compared to other clinical teams, individual antimicrobial conversion rates, and comparison to prior team progress (Figure 1). RePOrt Cards were provided through October 2021. This study compared pre-intervention days of therapy (DOTs) of antimicrobials from November 2019-October 2020 to post-intervention DOTs from November 2020 to March 2022. The primary objective of this study was to assess the impact of monthly, team-based feedback on percentage of antimicrobials administered orally during a pharmacist-driven IV to PO stewardship initiative. Figure 1Example RePOrt Card

Results

Significantly more DOTs were administered orally in the post intervention group (62% vs 67%, p=0.0012). Positive change in oral conversion rates was observed for all agents except linezolid, minocycline, and voriconazole (Table 1). The largest increase in percentage of DOT administered orally was observed for azithromycin (20%), rifampin (14%), and metronidazole (10%). Estimated monthly and total cost differences are available in Table 2. Minocycline represents the largest opportunity missed; while oral conversion rates remained the same, an increase in overall drug use creates opportunity to continue to prioritize oral conversion due to high cost.

Conclusion

Monthly, team-based feedback positively impacted IV to PO conversion rates. Opportunities remain to optimize cost benefits in high-cost agents such as linezolid, minocycline, and voriconazole.

Disclosures

Amy L. Carr, PharmD, BCIDP, Shionogi: Advisory Board.
920. Leveling Up: Evaluation of IV vs. PO Linezolid Utilization and Cost after an Antimicrobial Stewardship Program Revision of IV to PO Conversion Criteria within a Healthcare System
Authors: Jaggar Jessica H , Cleveland Kerry O , Twilla Jennifer D , Patterson Shanise , Hobbs Athena L V
Published: December 2022

Background

Intravenous (IV) to oral (PO) conversion is specifically listed as a pharmacy-based intervention in the CDC’s Core Elements of an Antimicrobial Stewardship Program (ASP). Due to linezolid’s high PO availability and high IV cost, it is used as a marker for pharmacist-driven IV to PO conversion within our healthcare system, which remained low despite the existence of a pharmacist-driven IV to PO protocol. The system ASP implemented an intervention aimed at improving rates of IV to PO conversion of antimicrobials.

Methods

This retrospective, observational cohort was conducted within a healthcare system composed of 5 adult acute care facilities. The system ASP reviewed and revised the conversion eligibility criteria November 30, 2021 (Table 1). Education was conducted, and a compulsory computerized training module was assigned to every pharmacist in the system. Two follow-up emails reporting results were also sent to the system ASP pharmacy leaders during the post-intervention period, and leaders were encouraged to share results with their departments. The primary objective of this study was to determine if there was a difference in PO linezolid utilization reported as days of therapy per 1000 patient days (DOT/1000 PD) between the pre- and post-intervention periods. Secondary objectives included IV linezolid utilization and cost savings.

Results

The average DOT/1000 PD for PO linezolid in the pre-intervention period (February-November 2021) was 38.9 compared to 58.8 for the post-intervention period (December 2021-March 2022), p< 0.01 (Figure 1). This reflected an increase in the average percentage of PO use from 42.9 to 62.4% for the pre- and post-intervention periods, respectively (p< 0.01, Figure 2). Inversely, the average DOT/1000 PD for IV linezolid fell from 52.1 to 35.4 in the pre- and post-intervention periods, respectively (p< 0.01). A cost savings analysis revealed a monthly post-intervention savings of $7,091.34 with a projected total annual cost savings of $85,096.09 for the system.

Conclusion

An ASP intervention that revised criteria for IV to PO conversion, educated pharmacists, and tracked and reported results led to significantly more PO linezolid use and reduced overall cost in a large healthcare system.

Disclosures

Kerry O. Cleveland, MD, AbbVIe: Honoraria|Merck: Honoraria.
931. All Hands on Deck: Incorporation of Infectious Diseases Pharmacy Trainees in a Community Hospital Antimicrobial Stewardship Program
Authors: Herald Fischer , Drwiega Emily N , Drwiega Emily N , Griffith Nikki , Burgos Rodrigo M , Mena Lora Alfredo J
Published: December 2022

Background

Community hospitals may have challenges implementing core elements of antimicrobial stewardship (ASP) due to lack of ID trained pharmacists (PharmD). The COVID-19 pandemic compounded these challenges with constrained resources and staffing. The pandemic also saw a rise in antimicrobial use (AU) and brought forth novel therapeutics, thus increasing the need for robust ASP. We established a community ASP rotation for ID PharmD fellows during the COVID-19 pandemic.

Methods

A community ASP rotation was established at a 151-bed community hospital. ID PharmD trainees rotated with the ID clinician and were responsible for daily prospective audit and feedback (PAF) under close supervision of the ID clinician. Fellows were involved in pandemic response, including protocol development and restrictions for COVID-19 therapeutics.

Results

A community ASP rotation was successfully implemented (Figure 1). For PAF activities, the most common indications were CAP (19%), HAP (3%), IAI (24%), SSTI (22%) and UTI (19%). Average DOT/1000 was 340.4 per quarter with increases each COVID-19 surge (Figure 2). Empiric AU was protocol adherent 77% of the time and 23% required ASP changes. ASP Interventions included change to protocol (23%), bug drug mismatch (2%), de-escalation (15%), duration change (25%), IV to PO (16%), discontinuation (19%). Fellows successfully developed protocols and managed restrictions for remdesivir, baricitinib, and anti-SARS-CoV-2 monoclonal antibodies in coordination with the ID clinician and assisted in mass vaccination campaign protocols.

Conclusion

A community ASP rotation was successfully established and sustained during COVID-19. Fellows received hands on experience and performed PAF under close supervision. The program enhanced ID clinician capabilities while leveraging PharmD expertise at a time when staffing and resources were stretched thin. The rotation provided firsthand experience in pandemic preparedness and response. This educational opportunity assisted in maintaining a strong ASP in a community hospital setting while preparing trainees with experiences to assist them throughout their future careers.

Disclosures

All Authors: No reported disclosures.