BACKGROUND:Growing evidence indicates antimicrobial resistance disproportionately affects individuals living in socially vulnerable areas. This study evaluated the association between the CDC/ATSDR Social Vulnerability Index (SVI) and Streptococcus pneumoniae (SP) antimicrobial resistance (AMR) in the United States. METHODS:Adult patients ≥18 years with 30-day nonduplicate SP isolates from ambulatory/hospital settings from January 2011 to December 2022 with zip codes of residence were evaluated across 177 facilities in the BD Insights Research Database. Isolates were identified as SP AMR if they were non-susceptible to ≥1 antibiotic class (macrolide, tetracycline, extended-spectrum cephalosporins, or penicillin). Associations between SP AMR and SVI score (overall and themes) were evaluated using generalized estimating equations with repeated measurements within county to account for within-cluster correlations. RESULTS:Of 8008 unique SP isolates from 574 US counties across 39 states, the overall proportion of AMR was 49.9%. A significant association between socioeconomic status (SES) theme and SP AMR was detected with higher SES theme SVI score (indicating greater social vulnerability) associated with greater risk of AMR. On average, a decile increase of SES, indicating greater vulnerability, was associated with a 1.28% increased risk of AMR (95% confidence interval [CI], .61%, 1.95%; P = .0002). A decile increase of household characteristic score was associated with a 0.81% increased risk in SP AMR (95% CI, .13%, 1.49%; P = .0197). There was no association between racial/ethnic minority status, housing type and transportation theme, or overall SVI score and SP AMR. CONCLUSIONS:SES and household characteristics were the SVI themes most associated with SP AMR.

Background Antibiotic usage and antibiotic resistance (ABR) patterns changed during the COVID-19 pandemic. Inadequate empiric antibiotic therapy (IET) is a significant public health problem and contributes to ABR. We evaluated factors associated with IET before and during the COVID-19 pandemic to determine the impact of the pandemic on antibiotic management. Methods This multicenter, retrospective cohort analysis included hospitalized US adults who had a positive bacterial culture (specified gram-positive or gram-negative bacteria) from July 2019 to October 2021 in the BD Insights Research Database. IET was defined as antibacterial therapy within 48 h that was not active against the bacteria. ABR results were based on susceptibility testing and reports from local facilities. Multivariate analysis was used to identify risk factors associated with IET in patients with any positive bacterial culture and ABR-positive cultures, including multidrug-resistant (MDR) bacteria. Results Of 278,344 eligible patients in 269 hospitals, 56,733 (20.4%) received IET; rates were higher in patients with ABR-positive (n = 93,252) or MDR-positive (n = 39,000) cultures (34.9% and 45.0%, respectively). Severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2)-positive patients had significantly higher rates of IET (25.9%) compared with SARS-CoV-2-negative (20.3%) or not tested (19.7%) patients overall and in the ABR and MDR subgroups. Patients with ABR- or MDR-positive cultures had more days of therapy and longer lengths of stay. In multivariate analyses, ABR, MDR, SARS-CoV-2-positive status, respiratory source, and prior admissions were identified as key IET risk factors. Conclusions IET remained a persistent problem during the COVID-19 pandemic and occurred at higher rates in patients with ABR/MDR bacteria or a co-SARS-CoV-2 infection.

Data evaluating cefepime thresholds associated with neurotoxicity remain limited. The objectives of this study were to evaluate the incidence of cefepime‐related neurotoxicity (CRN) in patients with plasma cefepime concentrations, assess the relationship between cefepime exposure and CRN, investigate clinical factors associated with CRN, and describe electroencephalogram (EEG) abnormalities in CRN.

Abstract Background Antibiotic resistant infections affect more than 2.8 million people in the US each year and disproportionately impact those who are socially vulnerable. The objective of this study was to evaluate the association between Streptococcus pneumoniae (SP) antimicrobial resistance (AMR) and the CDC/ATSDR Social Vulnerability Index (SVI) in the US. Methods Adult patients (≥ 18 years) with 30-day nonduplicate SP isolates from ambulatory/hospital settings from January 2011–December 2022 who had zip codes of residence reported were evaluated across 177 facilities in the BD Insights Research Database (Becton, Dickinson & Co., Franklin Lakes, NJ). Isolates were identified as SP AMR if they were intermediate or resistant to ≥ 1 macrolide, tetracycline, extended-spectrum cephalosporin, or penicillin. Isolates from adult patients with zip code of residence reported were matched with county-level CDC SVI data, and associations between SVI score (overall and by each theme) and SP AMR were evaluated using generalized estimating equations with repeated measurements within county to account for within-cluster correlations (Figure 1, Table 1). Results Of the 8,008 unique SP isolates linked to 574 US counties, the overall rate of SP AMR was 49.9%. A significant association between the socioeconomic status (SES) theme and SP AMR was detected with higher SVI scores (indicating greater social vulnerability) associated with greater risk of AMR. On average, a single decile increase in SES theme ranking score was observed to be associated with a 1.28% increased risk of AMR (95% confidence interval [CI], 0.61%, 1.95%; P=0.0002; Table 1). Similarly, a single decile increase in household characteristic theme ranking score was observed to be associated with a 0.81% increased risk in SP AMR (95% CI,0.13%, 1.49%; P=0.0197). However, no association between the racial and ethnic minority status theme, the housing type and transportation theme, and overall SVI score and SP AMR were observed. Conclusion Higher SES and household characteristic ranking scores (indicating greater social vulnerability) were observed to be associated with higher risk of SP AMR. These results contribute to evidence linking AMR to health disparities and inequities and suggest that AMR is impacted by social determinants of health. Disclosures Salini Mohanty, DrPH, MPH, Employee of Merck & Co., Inc.: Stocks/Bonds Gang Ye, PhD, Becton Dickinson and Company: employee Charles Sheets, MS, Becton Dickinson: Data Analysis Nicole Cossrow, PhD, Merck: Stocks/Bonds Kalvin Yu, MD, FIDSA, BD: Stocks/Bonds Meghan White, PharmD, Merck: Employee|Merck: Stocks/Bonds Kenneth P. Klinker, PharmD, Merck & Co., Inc: Employee|Merck & Co., Inc: Stocks/Bonds Vikas Gupta, PharmD, Becton, Dickinson and Company (BD): Employee of BD|Becton, Dickinson and Company (BD): Stocks/Bonds

Antimicrobial resistance is a global public health threat, and gram-negative bacteria, such as Enterobacterales and Pseudomonas aeruginosa, are particularly problematic with difficult-to-treat resistance phenotypes. To reduce morbidity and mortality, a reduction in the time to effective antimicrobial therapy (TTET) is needed, especially among critically ill patients. The antibiogram is an effective clinical tool that can provide accurate antimicrobial susceptibility information and facilitate early antimicrobial optimization, decrease TTET, and improve outcomes such as mortality, hospital length of stay, and costs. Guidance is lacking on how to validate the susceptibility to new antibacterial agents. Commonly used traditional and combination antibiograms may not adequately assist clinicians in making treatment decisions. Challenges with the current susceptibility testing of new β-lactam/β-lactamase inhibitor combinations persist, impacting the appropriate antibacterial choice and patient outcomes. Novel antibiograms such as syndromic antibiograms that incorporate resistant gram-negative phenotypes and/or minimum inhibitory concentration distributions may assist in determining the need for earlier susceptibility testing or help define an earlier optimal use of the new β-lactam/β-lactamase inhibitors. The purpose of this review is to emphasize novel antibiogram approaches that are capable of improving the time to susceptibility testing and administration for new β-lactam/β-lactamase inhibitors so that they are earlier in a patient's treatment course.

Abstract Background Antibacterial therapy is frequently used in patients with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) without evidence of bacterial infection, prompting concerns about increased antimicrobial resistance (AMR). We evaluated trends in AMR before and during the SARS-CoV-2 pandemic. Methods This multicenter, retrospective cohort analysis included hospitalized adults aged ≥18 years with >1-day inpatient admission and a record of discharge or death from 271 US facilities in the BD Insights Research Database. We evaluated rates of AMR events, defined as positive cultures for select gram-negative and gram-positive pathogens from any source, with nonsusceptibility reported by commercial panels before (1 July 2019–29 February 2020) and during (1 March 2020–30 October 2021) the SARS-CoV-2 pandemic. Results Of 5 518 666 admissions evaluated, AMR rates per 1000 admissions were 35.4 for the prepandemic period and 34.7 for the pandemic period (P ≤ .0001). In the pandemic period, AMR rates per 1000 admissions were 49.2 for SARS-CoV-2–positive admissions, 41.1 for SARS-CoV-2–negative admissions, and 25.7 for patients untested (P ≤ .0001). AMR rates per 1000 admissions among community-onset infections during the pandemic were lower versus prepandemic levels (26.1 vs 27.6; P < .0001), whereas AMR rates for hospital-onset infections were higher (8.6 vs 7.7; P < .0001), driven largely by SARS-CoV-2–positive admissions (21.8). AMR rates were associated with overall antimicrobial use, rates of positive cultures, and higher use of inadequate empiric therapy. Conclusions Although overall AMR rates did not substantially increase from prepandemic levels, patients tested for SARS-CoV-2 infection had a significantly higher rate of AMR and hospital-onset infections. Antimicrobial and diagnostic stewardship is key to identifying this high-risk AMR population.

Novel therapies for methicillin-resistant Staphylococcus aureus (MRSA) bloodstream infection (BSI) are needed in the setting of reduced antibiotic susceptibilities and therapeutic failure. Ceftaroline is a cephalosporin antibiotic with MRSA activity. Although not FDA approved for MRSA BSI, ceftaroline has generated much interest as a potential treatment option. However, detailed descriptions of its use in this setting remain limited. To address this, we conducted a retrospective, multicenter, observational study of adult patients with MRSA BSI treated with at least 72 h of ceftaroline from 2011 to 2015. Safety outcomes were examined in the overall cohort, while efficacy outcomes were examined among patients who had not cleared their BSI prior to ceftaroline initiation. Data were also stratified by ceftaroline monotherapy or combination therapy. Predictors of clinical failure on ceftaroline treatment were also sought. Overall, 211 patients were included in the safety population; Clostridium difficile infection, rash, and neutropenia occurred in 6 patients (2.8%), 7 patients (3.3%), and 3 patients (1.4%), respectively. Clinical success was observed in 86 (68.3%) of the 126 patients included in the efficacy population. The monotherapy and combination therapy subgroups had similar proportions of patients experiencing success (69.7 and 64.9%, respectively). The median BSI durations post-ceftaroline treatment were 2 days (interquartile range, 1 to 4 days) for monotherapy and 3 days (interquartile range, 1.5 to 5 days) for combination therapy. Higher acute physiology and chronic health evaluation II scores and comorbid malignancy independently predicted treatment failure. Ceftaroline appears effective for MRSA BSI as both monotherapy and combination therapy. However, comparative studies are needed to further delineate the role of ceftaroline in MRSA BSI treatment.

The 23-valent pneumococcal polysaccharide vaccine (PPSV23) targets 23 common serotypes and is recommended for use in adults in various countries to protect against pneumococcal infection. Test-negative design (TND) studies aim to include cases and controls from the same healthcare facilities; however, design choices or limitations associated with conducting real-world research can affect the study results. Here, we highlight how some methodological limitations may have affected results and conclusions of a published study described by Chandler et al.

BACKGROUND:Inpatient management of SSTIs utilizes considerable healthcare resources. The CREST+SEWS score categorizes patients with SSTIs into 4 severity classes. Hospitalizations can be avoided in Class I as they are treated as outpatients with oral antibiotics, whereas Class IV require hospitalization for intravenous antibiotics.OBJECTIVE:The purpose of this study was to perform a budget impact analysis on CREST+SEWS Class 1 patients, to compare the medical costs of current treatment, in the inpatient setting with intravenous antibiotics, with a proposed alternative of using oral antibiotics in the outpatient setting. Further, resource utilization in Class I was evaluated.METHODS:This was a retrospective study of adult patients hospitalized in 2015 for SSTIs who received >24 hours of antimicrobials. The CREST+SEWS scoring system was used to stratify patients into Class I to IV. Pharmacy and medical costs and resources associated with inpatient management of Class I SSTIs were derived from the itemized discharge records.RESULTS:Of the 252 patients who met the inclusion criteria, 61 (24%) were classified as Class I. The total cost of treating Class I SSTI patients in the inpatient setting was $281,816 (cost per patient: $4,619) in 2015 USD. In the hypothetical situation of treatment with oral antibiotics in the outpatient setting, the cost savings were estimated to be $4,398 per patient. Fifty-three percent of patients had blood cultures, and on average, each patient received 2 radiographic tests.CONCLUSIONS:Identifying outpatient candidates, and avoiding tests with low diagnostic can reduce the economic burden of SSTIs.

The rapid evolution of resistance, particularly among Gram-negative bacteria, requires appropriate identification of patients at risk followed by administration of appropriate empiric antibiotic therapy. A primary tenet of antimicrobial stewardship programs (ASPs) is the establishment of empiric antibiotic recommendations for commonly encountered infections. An important tool in providing empiric antibiotic therapy recommendations is the use of an antibiogram. While the majority of institutions use a traditional antibiogram, ASPs have an opportunity to enhance antibiogram data. The authors provide the rationale for why ASPs should implement alternative antibiograms, and the importance of incorporating an antibiogram into clinical decision support systems with the goal of providing effective empiric antibiotic therapy.

Abstract Background In the US, the burden of multidrug resistant bacterial infections, including carbapenem-resistant P. aeruginosa (CRPA) and ESBL-producing Enterobacterales (ESBL-E), is substantial. These resistant pathogens may affect the delivery of timely effective therapy. The aim of this study is to evaluate beta-lactam (BL) susceptibility trends based on the aggregate frequency of CRPA and a combined ESBL-E phenotype (K. pneumoniae (KPn) + E. coli (EC)) observed in critically ill patients with lower respiratory tract infections (LRTI). Methods In 2016-2019, ~20 US institutions per year submitted up to 250 gram-negative pathogens as part of the Study for Monitoring Antimicrobial Resistance Trends. A total of 871 PA, 380 KPn, and 336 EC isolates were collected from ICU patients with LRTI. MICs were determined using broth microdilution and interpreted using 2021 CLSI breakpoints. ESBL-E phenotype was defined as: ceftriaxone MIC ≥ 2 mcg/mL. Institutions were stratified into two groups based on frequency of CRPA and combined ESBL-E phenotype: Group 1: CRPA ≤ 15% and ESBL-E ≤ 15%; Group 2: CRPA > 15% and ESBL-E > 15%. Based on CLSI guidance, an empiric antibiotic susceptibility threshold of ≥90% was deemed optimal. Results Overall, CRPA and ESBL-E phenotypes were identified in 28.4% and 21.2% of isolates, respectively. Aggregate BL susceptibility in group 1 was above the 90% threshold for cefepime (FEP), piperacillin/tazobactam (TZP), meropenem (MEM), ceftolozane/tazobactam (C/T), and imipenem/relebactam (I/R) (Table 1). However, as frequency of CRPA and ESBL-E exceeded 15%, aggregate BL susceptibility declined to 77.3%, 79.3%, and 86.2% for FEP, TZP, and MEM, respectively. In contrast, C/T and I/R maintain susceptibility above the empiric susceptibility threshold. Table 1. Aggregate susceptibility of P. aeruginosa, E. coli, and K. pneumoniae ICU LRTI isolates stratified by resistance frequency: Best- (Group 1) and worst-case (Group 2) scenarios Conclusion In ICU patients, exceeding CRPA and combined ESBL-E phenotype frequency of 15% for both classifications, impacts susceptibility to 1st line BL’s resulting in a failure to achieve empiric susceptibility thresholds. This stratification could serve as a decision point for triggering earlier susceptibility testing or modifying empiric therapy recommendations for LRTI to include newer agents pending microbiology results. Disclosures Kenneth Klinker, PharmD, Merck & Co., Inc. (Employee, Shareholder) Levita K. Hidayat, PharmD BCIDP, Merck & Co., Inc. (Employee, Shareholder) C. Andrew DeRyke, PharmD, Merck & Co., Inc. (Employee, Shareholder) Mary Motyl, PhD, Merck & Co., Inc. (Employee, Shareholder) Karri A. Bauer, PharmD, Merck & Co., Inc. (Employee, Shareholder)

Abstract Background Due to variability in the precision of an MIC, concern may exist in optimizing PK/PD using standard doses when the MIC is at the susceptibility breakpoint (SBP). This is notable when treating infections in critically ill patients. Evaluating MIC distributions among commonly used antibiotics and accounting for isolates at the SBP represents an additional enhancement to inform empiric therapy. The aim of the study was to evaluate antibiotic susceptibility for commonly used β-lactams against Pseudomonas aeruginosa (PA) in a syndromic antibiogram, incorporating MIC distribution. Methods 20 US institutions submitted yearly up to 250 consecutive targeted Gram-negative pathogens from hospitalized patients as part of the Study for Monitoring Antimicrobial Resistance Trends (SMART) in 2016-2019. MICs were determined by broth microdilution and interpreted using 2021 CLSI breakpoints. The syndromic antibiogram included PA from a blood or respiratory source based on patient location. Based on CLSI guidance, an empiric antibiotic susceptibility threshold of ≥ 90% was deemed optimal. Results 2,500 PA blood (n=680) and respiratory (n=1,820) isolates were evaluated; piperacillin/tazobactam (P/T), cefepime (FEP), meropenem (MEM), and ceftolozane/tazobactam (C/T) susceptibilities were 69.6%, 74.2%, 75.3%, and 95%, respectively (Figure 1). Isolates with MICs at the SBP were observed in 12.1%, 18.7%, 7.5%, and 6.5% for P/T, FEP, MEM, and C/T, respectively. Susceptibilities were lower when stratified by ICU, 64.8%, 71.2%, 70.7%, and 93.7% for P/T, FEP, MEM, and C/T, respectively with a similar frequency of SBP isolates (Figure 2). Figure 1. Syndromic antibiogram evaluating P. aeruginosa blood and respiratory isolates. Figure 2. Syndromic antibiogram evaluating Pseudomonas aeruginosa blood and respiratory isolates stratified by ICU. *MIC breakpoints used to determine susceptibility included: P/T MIC ≤ 16/4 µg/ml, FEP ≤ 8 µg/ml, MEM ≤ 2 µg/ml, C/T ≤ 4 µg/ml Conclusion Our analysis demonstrated that first line antipseudomonal agents, P/T and FEP, have susceptibility rates lower than the CLSI recommended threshold. A significant portion of the MICs within the susceptible range are at the SBP. Due to the frequency of baseline resistance and challenge in achieving adequate PK/PD in critically ill patients, clinicians may be concerned with relying on certain antibiotics when the MIC is at the SBP. Antimicrobial stewardship programs should consider incorporating MIC distributions into syndromic antibiograms to better inform empiric therapy recommendations. Disclosures Karri A. Bauer, PharmD, Merck & Co., Inc. (Employee, Shareholder) Levita K. Hidayat, PharmD BCIDP, Merck & Co., Inc. (Employee, Shareholder) Kenneth Klinker, PharmD, Merck & Co., Inc. (Employee, Shareholder) Mary Motyl, PhD, Merck & Co., Inc. (Employee, Shareholder) C. Andrew DeRyke, PharmD, Merck & Co., Inc. (Employee, Shareholder)

Cefepime is commonly used in the intensive care unit (ICU) to treat bacterial infections. The time during which the free cefepime concentration is above the MIC ( f T >MIC ) should be optimized to increase the efficacy of the regimen. We aim to optimize the exposure of cefepime in ICU patients by using population pharmacokinetic (PK) modeling and simulations. Two data sets were included in this study. The first was a prospective study of pediatric patients who received cefepime at 50 mg/kg of body weight and had extensive PK sampling.

Purpose The goal of this review is to explore the role of antimicrobial therapeutic drug monitoring (TDM), especially in critically ill, obese, and older adults, with a specific focus on β-lactams and vancomycin. Summary The continued rise of antimicrobial resistance prompts the need to optimize antimicrobial dosing. The aim of TDM is to individualize antimicrobial dosing to achieve antibiotic exposures associated with improved patient outcomes. Initially, TDM was developed to minimize adverse effects during use of narrow therapeutic index agents. Today, patient and organism complexity are expanding the need for precision dosing through TDM services. Alterations of pharmacokinetics and pharmacodynamics (PK/PD) in the critically ill, obese, and older adult populations, in conjunction with declining organism susceptibility, complicate attainment of therapeutic targets. Over the last decade, antimicrobial TDM has expanded with the emergence of literature supporting β-lactam TDM and a shift from monitoring vancomycin trough concentrations to monitoring of the ratio of area under the concentration (AUC) curve to minimum inhibitory concentration (MIC). PK/PD experts should be at the forefront of implementing precision dosing practices. Conclusion Precision dosing through TDM is expanding and is especially important in populations with altered PK/PD, including critically ill, obese, and older adults. Due to wide PK/PD variability in these populations, TDM is vital to maximize antimicrobial effectiveness and decrease adverse event rates. However, there is still a need for studies connecting TDM to patient outcomes. Providing patient-specific care through β-lactam TDM and transitioning to vancomycin AUC/MIC monitoring may be challenging, but with experts at the forefront of this initiative, PK-based optimization of antimicrobial therapy can be achieved.

Abstract Background A primary tenet of antimicrobial stewardship programs (ASPs) is to establish empiric antibiotic treatment recommendations. While traditional antibiograms are useful, intrinsic variability in susceptibility exists when stratifying by source and/or location. In contrast, a syndromic antibiogram displays the likelihood of adequate coverage for a specific infection syndrome, considering the weighted incidence of pathogens causing that syndrome. The aim of the study was to compare antibiotic susceptibilities using a traditional versus syndromic antibiogram. Methods Between 2016–2019, 20 US institutions per year submitted up to 250 consecutive targeted gram-negative pathogens from hospitalized patients as part of the Study for Monitoring Antimicrobial Resistance Trends (SMART). MICs were determined by broth microdilution and interpreted using 2020 CLSI breakpoints, except for imipenem/relebactam (I/R) for which FDA breakpoints were used. The traditional antibiogram included the 3 most common Gram-negative pathogens from all sources and represented critical organisms considered for empiric antibiotic coverage; the syndromic antibiogram included the 3 most commonly isolated Gram-negative pathogens from a respiratory source based on patient location. Results 17,561 Gram-negative isolates, including 6,654 lower respiratory isolates were evaluated. The top 3 most common Gram-negative organisms included: E. coli (n=6095, 44%), Klebsiella spp. (n=4097, 30%), P. aeruginosa (n=3649, 26%). Cumulative susceptibilities were comparable using a traditional vs. syndromic antibiogram (Figure 1); however, cefepime (FEP), piperacillin/tazobactam (TZP), and meropenem (MEM) susceptibilities were 5 – 8% lower when stratified by patient location (Figure 2) and ≥10% for P. aeruginosa (Figure 3). Ceftolozane/tazobactam (C/T) and I/R demonstrated ≥90% susceptibility regardless of respiratory source or patient location. Figure 1. Cumulative susceptibility of E. coli, Klebsiella spp, and P. aeruginosa for traditional vs. syndromic antibiogram Figure 2. Syndromic antibiogram evaluating cumulative susceptibility of E. coli (n = 637), Klebsiella spp. (n = 1190) and P. aeruginosa (n = 1997) respiratory isolates stratified by patient location Figure 3. Syndromic antibiogram evaluating susceptibility of P. aeruginosa (n = 1997) respiratory isolates stratified by patient location Conclusion Our analysis demonstrated that susceptibilities were lower for first-line agents when stratified by ICU and P. aeruginosa. ASPs should consider syndromic antibiograms based on source and patient location to optimize empiric antibiotic therapy recommendations. Disclosures Kenneth Klinker, PharmD, Merck & Co, Inc (Employee) Karri A. Bauer, PharmD, Merck Research Laboratories (Employee) C. Andrew DeRyke, PharmD, Merck & Co., Inc. (Employee, Shareholder) Levita K. Hidayat, PharmD BCIDP, Merck & Co (Employee)

BACKGROUND:In the ICU, early and appropriate antimicrobial therapy is important to lower infection-related mortality. OBJECTIVES:Assess whether achieving early β-lactam free concentration above the MIC 100% of the time (fT>MIC) is associated with positive outcomes in the ICU. METHODS:This retrospective study was conducted in ICU patients admitted to UF Health Shands Hospital between 2016 and 2018. Adult patients who received β-lactam therapy and had drug concentration measured were included. Data collected included demographics, β-lactam regimens and concentrations, sources of infection, cultures and susceptibilities, mortality, length of stay, resistance acquisition for 30 days and clinical outcome at end of therapy. Multiple regression and time-to-event (TTE) analyses were performed. RESULTS:Two-hundred and six patients were included. Clinical cure occurred in 71%, microbial eradication occurred in 58% and new resistance to the β-lactam received developed in 8% of patients. Hospital and 30 day mortalities were 17% and 14%, respectively. fT>MIC and fT>4×MIC were associated with clinical cure (P = 0.0303), microbial eradication (P = 0.0476) and suppression of resistance (P = 0.0043). Delay in measuring β-lactam concentration was associated with clinical failure (P = 0.0072), longer ICU stay (P < 0.0001) and higher mortality (P = 0.0387). In the TTE analysis, patients with 100% fT>MIC had a significantly shorter ICU stay (P = 0.0297). Patients who had clinical cure and microbial eradication had drug concentrations measured earlier (P = 0.0025 and 0.0254, respectively). CONCLUSIONS:This study highlights the importance of early measurement of β-lactam concentration and confirms the association between fT>MIC and clinical cure, microbial eradication and emergence of resistance.

Two patients with normal renal function, yet each showed unexpected, supra- and subtherapeutic linezolid plasma concentrations resulting in toxicity and ineffective therapy, respectively. TDM helps to early identify and correct such excursions.

Background The incidence of cefepime-induced neurotoxicity (CIN) in hospitalized patients is highly variable. Although greater cefepime exposures incite neurotoxicity, data evaluating trough thresholds associated with CIN remains limited. The objectives of this study were to evaluate the incidence of CIN, assess the relationship between cefepime trough concentrations and CIN, investigate clinical factors associated with CIN, and describe electroencephalogram (EEG) abnormalities in CIN. Methods This was a retrospective study of adult patients who had received ≥ 5 days of cefepime with ≥ 1 trough concentration > 25 mg/L. Potential CIN cases were identified utilizing neurological symptoms, neurologist assessments, EEG findings and improvement of neurotoxicity after cefepime discontinuation. Results One-hundred and forty-two patients were included. The incidence of CIN was 13% (18/142). The mean cefepime trough concentration in CIN patients was significantly greater than the non-neurotoxicity group (74.2 mg/L ± 41.1 vs. 46.6 mg/L ± 23, p=0.015). Lower renal function (creatinine clearance < 30 ml/min), greater time to therapeutic drug monitoring (TDM) (≥72 hours), and each 1 mg/mL rise in cefepime trough were independently associated with increased risk of CIN. Moderate generalized slowing of the background rhythm was the most common EEG pattern associated with CIN. Conclusion Cefepime should be used cautiously in hospitalized patients due to the risk of neurotoxicity. Patients with greater renal function and those who had early cefepime TDM (≤ 72 hours) had lower risk of CIN.

Abstract Background Carbapenem-resistant P. aeruginosa (CRPA) are associated with increased mortality and impose significant treatment challenges for clinicians. Among CRPA, co-resistance to 1st line antipseudomonal agents piperacillin/tazobactam (TZP) and cefepime (FEP) is common and often results in delays to timely effective therapy. A simple strategy for identifying patients at risk for suboptimal therapy is evaluation of institutional or unit specific frequency of CRPA. The purpose of this analysis is to identify beta-lactam (BL) susceptibility trends based on CRPA frequency observed in intensive care units (ICU). Methods In 2016-2019, ~20 US institutions per year submitted up to 250 consecutive, aerobic or facultatively anaerobic, gram-negative pathogens from blood, intra-abdominal, urinary, and lower respiratory tract infections as part of the Study for Monitoring Antimicrobial Resistance Trends. A total of 871 P. aeruginosa (PA) isolates were collected from lower respiratory tract specimens obtained from ICU patients. MICs were determined using CLSI broth microdilution method and interpreted with CLSI 2020 or FDA breakpoints. Institutions were then stratified into one of three categories based on CRPA frequency: CRPA rates ≤20% (CR1), 21 – 40% (CR2), and ≥41% (CR3). BL susceptibility was then evaluated relative to CRPA frequency. Results Thirty-seven (46%), 25 (31%), and 18 (23%) institutions were stratified into CR1, CR2, and CR3, respectively. Overall, CRPA was identified in 28.4% of all ICU lower respiratory isolates. Significant declines in FEP and TZP susceptibility were observed in institutions that demonstrated higher CRPA frequency (p< 0.00001) (Table 1) with >25% of isolates showing resistance in CR2 and CR3. In contrast, C/T susceptibility remained above 90% for all categories. I/R susceptibility remained above 90% for CR1 and CR2. Table 1. P. aeruginosa susceptibility among ICU lower respiratory tract isolates stratified by unit specific frequency of carbapenem resistance Conclusion C/T and I/R provide robust activity against PA isolates obtained from the lower respiratory tract of critically ill patients, regardless of CR frequency. Assessing CRPA frequency may be useful for identifying inflection points in which novel agents could be considered. In settings where CRPA frequency exceeded 20%, additional testing or early switch to C/T or I/R may be warranted. Disclosures Kenneth Klinker, PharmD, Merck & Co, Inc (Employee) Daryl DePestel, PharmD, BCPS-ID, Merck & Co, Inc (Employee) Mary Motyl, PhD, Merck & Co, Inc (Employee, Shareholder) C. Andrew DeRyke, PharmD, Merck & Co., Inc. (Employee, Shareholder)

Abstract Background Based on prior studies, elderly patients and those with renal dysfunction are prone to cefepime (CFP) toxicity. The toxicokinetics and toxicodynamics for CFP are not well established. Lamoth et al. reported a 50% probability of CFP neurotoxicity at a serum trough concentration of ≥22 mg/L, whereas Huwyler et al. observed CFP neurotoxicity when concentrations exceeded 35 mg/L. The objectives of this study were to quantify the incidence of CFP neurotoxicity and to assess the association between CFP concentrations and neurotoxicity. Methods We conducted a retrospective review between March 2016 and May 2018, of adult patients with serum CFP trough concentrations ≥25 mg/L. To be considered a CFP neurotoxicity case, patients were required to fulfill at least two of the NCI criteria for neurological toxicity such as, presence of new-onset confusion, delirium, or drowsiness. Following this, cases were classified as (1) high likelihood of toxicity (HLT) if they either had a neurology consult or EEG findings consistent with CFP toxicity and if their symptoms improved after discontinuation of CFP, (2) possible toxicity (PT) if neurology consult or EEG was absent or if we were unable to assess improvement after CFP was discontinued, or (3) nontoxicity (NT). Cases were independently reviewed by an ID pharmacist and physician. Additional data such as comorbidities, renal function, and use of anti-epileptics were collected. Results One hundred and forty-two patients were included in the analysis. Neurotoxicity (HLT+PT) related to CFP occurred in 18/142 (13%) patients; 67% (12/18) were considered HLT. The median age in the HLT cohort was 68 years (interquartile range [IQR], 57–74), with toxicity occurring a median of 6 days (IQR, 5–8) after starting CFP. At the time of neurotoxicity, HLT patients had diminished renal function with a median SCr of 1.6 mg/dL (IQR, 1.2–2.4) and a corresponding CrCl of 35.8 mL/minute (IQR, 19.2–50.9). The median CFP trough concentration in the HLT patients was 62 mg/L (IQR, 50–73) vs. 70mg/L (IQR, 41–115) in the PT and 42 mg/L (IQR, 31–61) in the NT groups. Conclusion Our data emphasize the need for careful dosing in older patients with renal insufficiency. Interestingly, our study reveals higher cefepime troughs (~3-fold higher) associated with neurotoxicity than previously reported. Disclosures All authors: No reported disclosures.