Clinical Utility and Cost Effectiveness of Long-Acting Lipoglycopeptides Used in Deep-Seated Infections among Patients with Social and Economic Barriers to Care

The use of long-acting lipoglycopeptides (LaLGPs) in serious, deep-seated infections is of increasing interest. The purpose of this study is to evaluate the economic and clinical utility of LaLGPs in patients requiring protracted antibiotic courses who are not ideal candidates for oral transition or outpatient parenteral antibiotic therapy (OPAT). This is a retrospective, observational, matched cohort study of adult patients who received a LaLGP. Patients were matched 1:1 to those who received standard of care (SOC). Cost effectiveness was evaluated as total healthcare-related costs between groups. Clinical failure was a composite endpoint of mortality, recurrence, or need for extended antibiotics beyond planned course within 90 days of initial infection. There was no difference in clinical failure between the two cohorts (22% vs. 30%; p = 0.491). Six patients in the SOC cohort left against medical advice (AMA) prior to completing therapy. Among those who did not leave AMA, receipt of LaLGPs resulted in a decreased hospital length of stay by an average of 13.6 days. The average total healthcare-related cost of care was USD 295,589 in the LaLGP cohort compared to USD 326,089 in the SOC cohort (p = 0.282). Receipt of LaLGPs may be a beneficial treatment option for patients with deep-seated infections and socioeconomic factors who are not candidates for oral transition or OPAT.

Population Pharmacokinetics of Intravenous Amoxicillin Combined With Clavulanic Acid in Healthy and Critically Ill Dogs

Background: Data regarding antimicrobial pharmacokinetics (PK) in critically ill dogs are lacking and likely differ from those of healthy dogs. The aim of this work is to describe a population PK model for intravenous (IV) amoxicillin–clavulanic acid (AMC) in both healthy and sick dogs and to simulate a range of clinical dosing scenarios to compute PK/PD cutoffs for both populations.Methods: This study used a prospective clinical trial in normal and critically ill dogs. Twelve client-owned dogs hospitalized in the intensive care unit (ICU) received IV AMC 20 mg/kg every 8 h (0.5-h infusion) during at least 48 h. Eight blood samples were collected at predetermined times, including four trough samples before the next administration. Clinical covariates and outcome were recorded, including survival to discharge and bacteriologic clinical failure. Satellite PK data were obtained de novo from a group of 12 healthy research dogs that were dosed with a single AMC 20 mg/kg IV. Non-linear mixed-effects model was used to estimate the PK parameters (and the effect of health upon them) together with variability within and between subjects. Monte Carlo simulations were performed with seven dosage regimens (standard and increased doses). The correlation between model-derived drug exposure and clinical covariates was tested with Spearman's non-parametric correlation analysis. Outcome was recorded including survival to discharge and bacteriologic clinical failure.Results: A total of 218 amoxicillin concentrations in plasma were available for healthy and sick dogs. A tricompartmental model best described the data. Amoxicillin clearance was reduced by 56% in sick dogs (0.147 L/kg/h) compared with healthy dogs (0.336 L/kg/h); intercompartmental clearance was also decreased (p <0.01). None of the clinical data covariates were significantly correlated with individual exposure. Monte Carlo simulations showed that higher PK/PD cutoff values of 8 mg/L could be reached in sick dogs by extending the infusion to 3 h or doubling the dose.Conclusions: The PK of AMC is profoundly different in critically ill dogs compared with normal dogs, with much higher interindividual variability and a lower systemic clearance. Our study allows to generate hypotheses with regard to higher AMC exposure in clinical dogs and provides supporting data to revise current AMC clinical breakpoint for IV administration.

1425. Revisiting β-Lactams for Treatment of Uncomplicated Urinary Tract Infections: Evaluation of Twice-daily Cephalexin for Empiric Treatment of UTIs

Background Current IDSA guidelines for the treatment of UTIs discourage oral β-lactams based on lack of adequately powered studies to assess efficacy compared to fluoroquinolones or TMP-SMX. However, increasing E. coli and Klebsiella spp. resistance to first-line antibiotics has necessitated the need for alternative agents. Methods This was a single-center retrospective chart review of adult patients discharged from the University of New Mexico ED with twice-daily cephalexin for the treatment of uncomplicated UTIs from January 1, 2019 to December 31, 2019. Patients were excluded if < 18 years of age, received ≥ 10 days of cephalexin, received antibiotics for other indications, received antibiotics within 60 days prior to ED visit, or had structural abnormalities. The primary outcome of this study was the proportion of patients with clinical success 30 days after discharge from the ED. Patients not meeting criteria for clinical failure were classified as clinical success. Clinical failure was defined as return of patient within 30 days due to non-resolving or worsening UTI symptoms or change in antibiotic therapy after discharge based on urine culture and susceptibilities. Results A total of 264 patients were included for evaluation. The average age was 56.0 ± 20.2 years and 82.6% were female. Patients received an average 5.6 ± 0.9 days of antibiotic therapy including IV therapy. Of the 264 patients included for evaluation, 81.1% met criteria for clinical success. Of the patients with clinical failure, 29 (13.6%) required a change in antibiotics based on cultures and sensitivities, 17 (6.4%) returned for non-resolving or worsening symptoms, and 4 (1.5%) required both a change in antibiotics and returned for non-resolving or worsening symptoms. Conclusion Short courses of twice-daily cephalexin appear to be safe and effective for empiric treatment of uncomplicated UTIs. Adding β -lactams back to the antibiotic armamentarium for UTI treatment may delay the development of resistance to non- β -lactam antibiotics, ensuring their future utility. Disclosures All Authors: No reported disclosures

594. Micafungin Prophylaxis in Acute Myeloid Leukemia Adult Patients Undergoing Induction Chemotherapy

Background Patients (pts) with newly diagnosed acute myeloid leukemia (AML) undergoing induction chemotherapy are at increased risk for invasive fungal infections (IFI). Guidelines recommend posaconazole prophylaxis (ppx), but use is precluded by interactions and adverse effects. Micafungin (MCF) is an alternative, but data is limited by small prospective and retrospective studies. Primary objective: describe incidence of probable/proven IFI until neutrophil recovery (ANC ≥ 500 cells/µL) or 28 days after induction start date, whichever occurred first, in pts receiving MCF ppx. Secondary objective: describe incidence of clinical failure to MCF prophylaxis. Methods Retrospective review (January 2017 to January 2020) of newly diagnosed AML adult pts undergoing 7 + 3 using idarubicin (7 + 3-ida), 7 + 3 using daunorubicin (7 + 3-dau), venetoclax/decitabine (VEN/DEC), or venetoclax/azacitadine (VEN/AZA) receiving MCF ppx for at least 7 days included. Diagnosis of IFI < 30 days prior to induction, liver function tests (LFT) 5x ULN at start of induction, or evidence of refractory disease after induction excluded. Probable/proven IFI defined by EORTC criteria. Clinical failure: changing to a different antifungal class for any reason until ANC recovery or 28 days after induction start date. Results Ninety-five pts included. Baseline characteristics: mean (±SD) age 57.8 (±13.0) years; 53.6% males. 62% (59/95) 7 + 3-ida, 13.7% (13/95) 7 + 3-dau, 15.8% (15/95) VEN/DEC, 8.4% (8/95) VEN/AZA. Mean (±SD): 32.5% (±26) blasts, WBC 13.2 (±23.8), ANC 2.4 (±4.6), ALC 1.9 (±1.6), platelets 92.6 (±123.2). Incidence of probable IFI 2/95 (2.1%). No proven IFI cases identified. Clinical failure occurred in 37/95 (39%): 8 persistent febrile neutropenia, 29 due to suspected IFI. No MCF discontinuation due to adverse events. Conclusion Our findings suggest that prophylactic MCF is safe and effective in pts with newly diagnosed AML undergoing induction chemotherapy. Outcomes were similar to those of prophylactic posaconazole studies, indicating MCF may be considered as an alternative when interactions and adverse effects preclude use of posaconazole. Our study was limited by small numbers, retrospective, single-center design. Future opportunities include prospective trials of prophylactic MCF in this setting. Disclosures All Authors: No reported disclosures

193. Evaluation of Severity Scores in Patients with Methicillin-Susceptible Staphylococcus aureus Bloodstream Infections

Background Staphylococcus aureus bloodstream infections (BSIs) are associated with increased morbidity, mortality, and healthcare costs. Severity of illness scores help stratify critically ill patients and assist providers in making decisions. The quick Pitt (qPitt) score is a reliable predictor of mortality in patients with Gram-negative BSIs (AUROC 0.85); however, limited data exist for using the qPitt in methicillin-susceptible S. aureus (MSSA) BSIs. Methods This retrospective cohort evaluated patients with MSSA BSIs. The primary outcome was the discrimination of the qPitt in predicting hospital mortality compared to the Pitt bacteremia score (PBS). Secondary outcomes were clinical failure and the predictive discrimination of the qPitt score in comparison to other severity scoring modalities. Categorical data were analyzed using chi-square test or Fisher’s exact test. Continuous data were analyzed using Student’s t-test or Mann-Whitney U. Predictive discrimination was determined by the area under receiver operating characteristic curve. Results One hundred patients were included with the mean age of 52 years (p=0.84) and a BMI of 30 kg/m2. Males were predominant (70%). Mortality occurred in 13 patients who had more ICU admissions (92% vs. 37%; p< 0.01) and longer ICU LOS (10 vs. 5 days; p=0.03) despite similar baseline comorbidities. Time to definitive therapy was longer in the mortality group than non-mortality group (28 vs. 23 hours; p=0.79) though antimicrobial use did not differ. As outlined in Figure 1, the mortality group had higher severity of illness scores. The qPitt had a ROC of 0.83, indicating high discrimination. Overall, qPitt was found to be similarly predictive than PBS, equally as predictive as qSOFA, and more predictive than SIRS and APACHE II (Figure 1). Clinical failure occurred in 23% of patients; 54% of the mortality group experienced persistent BSI vs. 11% in the non-mortality group (p< 0.01), and 3% of the non-mortality group had recurrent infection (p=1.00). Conclusion Compared to previous studies on Gram-negative BSIs, the qPitt performed similarly in MSSA BSIs. The qPitt can be considered for use in predicting mortality for patients with MSSA BSIs; however, further studies are needed to confirm these results. Disclosures All Authors: No reported disclosures

185. Does an Infectious Diseases Consultation Improve Clinical Outcomes and Treatment Bundle Adherence for Enterococcal Bacteremia in a Multicenter Healthcare System?

Background Infectious diseases consultation (IDC) for Staphylococcus aureus bacteremia has a known mortality benefit, but for other gram positive bacteremias the benefit is not known. This study examined differences in outcomes for enterococcal bacteremia when management includes IDC. Methods This retrospective multicenter observational cohort study included adults with at least 1 positive blood culture with Enterococcus species. Patients who died or transferred to palliative care within 2 days of positive blood cultures were excluded. The primary outcome was a composite of clinical failure, including persistent blood cultures or fever for 5 days and in-hospital mortality. Secondary outcomes included adherence to a treatment bundle (appropriate empiric/definitive antibiotics, echocardiography (ECHO), duration of treatment, and repeat blood cultures). Results A total of 250 patients were included. IDC was obtained in 62.0% of patients. More patients in the IDC group had endocarditis (20% vs 0%, p < 0.0001) and bone and joint infections (13.5% vs 1.1%, p = 0.001), compared to more UTI (16.8% vs 39.0%, p < 0.0001) in the non-IDC group. Patients in the IDC group had more murmurs on initial exam (21.3% vs 6.3%, p = 0.002), prosthetic device (49.7% vs 27.4%, p = 0.001), and NOVA scores of ≥ 4 (40.6% vs 18.9%, p < 0.0001). Most infections were due to E. faecalis (78.4%) and most were susceptible to vancomycin and ampicillin at 90.4% and 92.4%, respectively. The composite of clinical failure occurred in 22.6% of patients with IDC and 16.8% in the non-IDC group (p=0.274). There was higher adherence to the treatment bundle in the IDC group (Figure 1). More patients in the IDC group were treated with ampicillin (47.1% vs 22.1%, p < 0.0001), and numerically more patients received treatment with vancomycin in the non-IDC group (17.4% vs 24.2%, p = 0.068). In the multivariate analysis, vasopressors were the only independent predictor of the primary outcome (OR 9.3, 95% CI 3.5-24.8, p < 0.0001). Figure 1. Adherence to treatment bundle. IDC = infectious diseases consultation, Echo = echocardiogram, * = p < 0.05 Conclusion There was no difference in rates of composite failure in patients with or without IDC; however, adherence to a treatment bundle was higher in the IDC group. IDC demonstrated stewardship benefits with regards to vancomycin usage. Disclosures All Authors: No reported disclosures

1074. The Relationship Between the Patient’s Body Mass Index and Dalbavancin’s Efficacy in the Treatment of Invasive Gram-Positive Infections

Background Dalbavancin is a long-acting lipoglyopeptide antibiotic used in the treatment of invasive gram-positive infections. There is a lack of published research on the effect of obesity on dalbavancin’s pharmacokinetics. The primary objective was to determine if obesity correlates to clinical failure at 90 days for patients with gram-positive infections treated with dalbavancin. Methods This retrospective observational study reviewed the use of dalbavancin from 1/1/2015- 3/31/2021 at 2 community hospitals. Patients were included if ≥ 18 years and received at least one dose of dalbavancin as an inpatient or at an outpatient infusion center. Patients were excluded if not seen by a provider within 90 days post last infusion. The primary outcome was clinical failure (CF). CF at 90 days was a composite of one or more of the following: need for additional antibiotics, dalbavancin intolerance, hospital readmission for same indication, need for additional surgery/debridement, or death. Clinical cure (CC) was defined as not meeting the criteria for CF. Patient demographics, BMI, indication, achievement of source control, Charlson Comorbidity Index (CCM) were collected. Descriptive statistics were used. To determine if a BMI cut-point exists between CC and CF, a classification & regression tree (CART) analysis was performed. Results A total of 81 patients received dalbavancin with 19 patients excluded for lack of follow up. Patient demographics: mean age (SD) 45.3 (15.8) years, 50% male; CCM 2.6 (3.1). Indications included osteomyelitis n=22, endovascular n=12, diabetic foot/skin soft tissue n=9, septic joint n=8, other n=11. A total of 29 (47%) of patients were bacteremic; 34 (55%) having source control. CF occurred in 15 of 62 (24%) patients. CF was compared with weight, BMI, CCM, albumin and source control. A difference existed in the median (IQR) BMI between CF 32.5 kg/m2 (25.1 – 42.8) and CC 25.5 kg/m2 (22.1 – 28.2); p=.029. A BMI cutpoint was not identified in CART analysis. Conclusion There is a relationship between increased BMI and 90-day CF in patients treated with dalbavancin. A higher BMI was found among those with with CF. Future studies are necessary to determine if a BMI based weight adjustment is necessary. Disclosures Lisa Avery, PharmD, BCPS, BCIDP, Merck (Other Financial or Material Support, Spouse Employer)

638. The Impact of in vitro Synergy Between Colistin and Meropenem on Clinical Outcomes in Invasive Carbapenem-resistant Gram-negative Infections: A Report from the OVERCOME Trial

Background Consensus guidelines caution against colistin (COL) monotherapy due to efficacy and resistance development concerns. The COL + meropenem (MEM) combination often displays in vitro synergy against carbapenem-resistant (CR) Gram-negative bacilli (GNB). We recently completed a clinical trial comparing outcomes in patients receiving COL vs. COL + MEM. Herein we assess if, amongst patients receiving COL + MEM, outcomes differed as a function of the presence (or absence) of in vitro synergy against the index pathogen. Methods OVERCOME was an international, multicenter, randomized, double-blind, placebo-controlled study comparing COL + placebo and COL + MEM for the treatment of pneumonia and/or bloodstream infection (BSI) due to CR GNB. Baseline isolates were COL susceptible (MIC ≤ 2 mg/L) and underwent synergy testing to COL + MEM in 24-hour time kill experiments (TKE). Synergy was defined as a >2-log CFU/ml reduction with combination therapy compared to the most active single agent. Outcomes assessed included 28-day mortality, clinical failure, and the development of COL resistance (MIC ≥ 4 mg/L) for both the overall cohort and the subgroup with A. baumannii. Results Of the 211 patients who received COL + MEM in OVERCOME, 186 had baseline synergy testing performed and were eligible for this analysis. The median age of the cohort was 70 years, 35% were female, 48% were white, and 44% Asian. Sixty-eight percent were in the intensive care unit (ICU) at infection onset. A. baumannii was the most common pathogen (78%) and pneumonia was the most common infection (68%). Synergy was demonstrated in most isolates (76%). Baseline characteristics, clinical, and microbiological outcomes were similar amongst patients infected with isolates against which COL + MEM demonstrated synergy and those where no synergy was demonstrated (Table 1). In patients with A. baumannii infections, the presence of in vitro synergy was associated with a decrease in clinical failure (53% vs. 79%; p = 0.04). No significant impact of synergy on 28-day mortality or development of COL resistance was demonstrated (Table 2). Conclusion The presence of in vitro synergy via TKE was associated with a decrease in clinical failure in patients treated with COL + MEM for invasive infections due to CR A. baumannii. Disclosures Jason M Pogue, PharmD, BCPS, BCIDP, Merck (Consultant)QPex (Consultant)Shionogi (Consultant)Utility Therapeutics (Consultant)VenatoRX (Consultant) Michael J. Rybak, PharmD, MPH, PhD, Paratek Pharmaceuticals (Research Grant or Support) Emmanuel Roilides, MD, PhD, FIDSA, FAAM, FESCMID, Merck Sharp & Dohme Corp. (Consultant, Grant/Research Support) Matthew Sims, MD, PhD, Astra Zeneca (Independent Contractor)Diasorin Molecular (Independent Contractor)Epigenomics Inc (Independent Contractor)Finch (Independent Contractor)Genentech (Independent Contractor)Janssen Pharmaceuticals NV (Independent Contractor)Kinevant Sciences gmBH (Independent Contractor)Leonard-Meron Biosciences (Independent Contractor)Merck and Co (Independent Contractor)OpGen (Independent Contractor)Prenosis (Independent Contractor)Regeneron Pharmaceuticals Inc (Independent Contractor)Seres Therapeutics Inc (Independent Contractor)Shire (Independent Contractor)Summit Therapeutics (Independent Contractor)