Antipseudomonal Β-lactams Research Articles

834. Clinical Outcomes with Carbapenem-Resistant Pseudomonas aeruginosa that Retain Susceptibility to Traditional Antipseudomonal β-lactams: Atlanta, 2016-2018

BackgroundCarbapenem-resistant Pseudomonas aeruginosa (CRPA) often results from multiple mechanisms, creating unique phenotypic patterns of resistance including retaining susceptibility to traditional antipseudomonal β-lactams: cefepime (FEP), ceftazidime (CAZ) and piperacillin-tazobactam (TZP). Outcomes of patients with CRPA susceptible to FEP, CAZ and TZP are unclear.MethodsThe Georgia Emerging Infections Programed performs active, population-based surveillance for CRPA (minimum inhibitory concentration [MIC] ≥ 8 µg/mL for doripenem, imipenem or meropenem) isolated from sterile sites, urine, lower respiratory tracts and wounds in metropolitan Atlanta. We created a retrospective cohort of adults without cystic fibrosis with their first episode of CRPA while hospitalized or hospitalized within 1 week, from 8/2016 – 7/2018. We compared patients with CRPA that remained susceptible to FEP, CAZ and TZP (“susceptible CRPA”) to those that were not (“resistant CRPA”) including multivariable logistic regression for 30-day mortality.ResultsAmong 643 patients, 638 had susceptibility results available for FEP, CAZ or TZP. 60% were male, median age was 65 years, and median Charlson comorbidity index was 2 (Table 1). Most (66%) resided in a hospital or long-term care facility 4 days prior to culture. The most common source was urine (38%). Non-susceptibility to multiple antibiotic classes was common: 523 (81%) for 3 classes and 214 (33%) for 5 classes (Table 2). 220 (34%) patients had susceptible CRPA and compared to patients with resistant CRPA, were more likely to have lived in a private residence, have a community-associated infection, and less likely to be in the ICU previously (Table 1). Patients with susceptible CRPA had a similar crude 30-day mortality (16% vs 12%, p = 0.15) to those with resistant CRPA, but in a multivariable analysis had an increased 30-day mortality (OR 1.9; 95% CI 1.1–3.2).Table 1 (Part 1/2): Characteristics and outcomes of hospitalized patients with carbapenem-resistant Pseudomonas aeruginosa (CRPA) in metropolitan Atlanta, stratified by antipseudomonal β-lactam susceptibility Table 1 (Part 2/2): Characteristics and outcomes of hospitalized patients with carbapenem-resistant Pseudomonas aeruginosa (CRPA) in metropolitan Atlanta, stratified by antipseudomonal β-lactam susceptibility Table 2: Antibacterial susceptibility results for hospitalized patients with carbapenem-resistant Pseudomonas aeruginosa in metropolitan Atlanta ConclusionOver 1/3 of hospitalized patients with CRPA retained susceptibility to other antipseudomonal β-lactams, but had an increased mortality compared to CRPA resistant to other β-lactams. Further research into mechanisms of resistance or antibiotics received might help explain this unexpected finding.Disclosures Jessica Howard-Anderson, MD, Antibacterial Resistance Leadership Group (ARLG) (Other Financial or Material Support, The ARLG fellowship provides salary support for ID fellowship and mentored research training)

1623. Outcomes of Critically Ill Adults, Hospitalized Patients (Pts) with Pseudomonas aeruginosa (PSA) Hospital- and Ventilator-Associated Pneumonia (HAP/VAP) Who Received an Active Anti-Pseudomonal β-Lactam (ASPB): Does “S” Equal Success in the Presence of Resistance to other ASPB?

BackgroundThe most commonly prescribed antibiotics for PSA HAP/VAP are ASPBs: meropenem (MER), piperacillin/tazobactam (TZP),cefepime (FEP) and ceftazidime (CAZ). Similar resistance mechanisms in PSA affect these agents, and it is unclear if you can use a susceptible ASPB when the PSA is resistant to other ASPBs. This study evaluates the impact of ASPB resistance among pts with PSA HAP/VAP who initially received therapy with an ASPB to which PSA was susceptible.MethodsA cohort study of Kaiser Permanente Southern California (KPSC) members (1/1/11-12/31/17) was performed. Inclusion criteria: (1) age ≥ 18 years; (2) HAP/VAP diagnosis; (3) monomicrobial PSA on a clinical respiratory culture (index PSA); (4) ICU at index PSA; (5) received MER, TZP, FEP or CAZ within ≤ 2 days of index PSA; (6) index PSA was susceptible to ASPB received; (7) no cystic fibrosis; (8) survived > 2 days post index PSA, and (9) ≥ 6 months of KPSC membership prior to index PSA. Pts were stratified by presence of resistance to MER, TZP, and FEP on index PSA (0 vs. ≥1 resistant ASPB). Outcomes: 30-day mortality and discharge to home.Results560 patients were included. Mean (SD) age was 70.5 (14.2) years, 60% were male, and most had many comorbidities. Thirty-day mortality was 28%, and 32% were discharged home. Ninety-five (17%) received an active ASPB for PSA HAP/VAP that was resistance to ≥ 1 ASPB. Relative to pts with no ASPB resistance, pts with resistance ≥ 1 ASPB had higher 30-day mortality (32% vs. 27%) and were less likely to be discharged home (17% vs. 35%). In multivariate analyses, pts with resistance ≥ 1 ASPB had higher 30-day mortality (aOR=1.61 [CI: 1.01-2.56]) and were less likely to be discharged home (aHR [95%]: 0.5 [0.3-0.9]).Crude and Adjusted Associations Between Presence of Anti-Pseudomonal β-Lactam -Resistance (Reference= no ASPB resistance) and Outcomes among Adult, ICU patients with HAP/VAP due to PSA who received a Microbiologic Active Anti-Pseudomonal β-Lactam ConclusionDespite receiving a microbiologic active agent within ≤ 2 days of their PSA HAP/VAP, pts with PSA that were resistant to ≥ 1 ASPB had worse outcomes relative to those that had no ASPB resistance. Further study is needed, but these findings suggest that the full ASPB susceptibility profile needs to be considered when selecting therapy for pts with PSA HAP/VAP. More studies are also needed to determine if alternative or combination therapies may be needed to maximize outcomes in PSA infection when there is resistance ≥ 1 ASPB.DisclosuresThomas Lodise, PharmD, PhD, Paratek Pharmaceuticals, Inc. (Consultant) Laura A. Puzniak, PhD, Merck (Employee) Rong Wei, MA, Kaiser Permenante (Research Grant or Support) Yun Tian, MS, Merck (Research Grant or Support) Theresa M. Im, MPH, Merck (Research Grant or Support) Lie Hong Chen, DrPH, Merk (Research Grant or Support) Sara Tartof, PhD, Merck (Grant/Research Support)

107. Impact of a Rapid Blood Culture Identification Panel at a Community Teaching Hospital: a Pre-Post Quasi-Experiment

BackgroundRapid diagnostic tests (RDT) for positive blood cultures can lead to quicker identification of organisms and key resistance elements. As a result time to targeted therapy may decrease, thus reducing the duration of broad, empiric antibiotic use. The purpose of this study was to determine the impact of implementing the BioFire® FilmArray® Blood Culture Identification (BCID) Panel for gram-positive organisms on antimicrobial process measures and patient outcomes at an academic community hospital.MethodsThis was a single-center, pre-post intervention, quasi-experimental study evaluating hospitalized adult patients who had at least one positive blood culture with gram-positive organisms from June 1, 2018 to August 31, 2018 and June 1, 2019 to August 31, 2019. Patients in the pre-intervention group were randomized and post-intervention patients were matched by identified organism. The primary outcome was the time to targeted therapy from blood culture collection. Secondary outcomes included time to targeted therapy from positive Gram stain, vancomycin and anti-pseudomonal β-lactam length of therapy (LOT), institutional vancomycin days of therapy (DOT), length of stay (LOS), and estimated hospitalization costs.ResultsA total of 75 patients in each group were included. The time to targeted therapy from blood culture collection was significantly decreased after RDT implementation [32.9 (23.2–51.8) hours vs. 49.2 (37.1–76.3 hours, p < 0.001)], as was time to targeted therapy from Gram stain results [8.5 (0–25.2) hours vs. 30 (19.4–52.9) hours, p < 0.001]. No difference was found between the groups with respect to LOS or estimated hospitalization cost. Overall the vancomycin LOT [0.86 (0.09–2.38) days vs. 2.18 (1.37–4.34) days, p = 0.001] and anti-pseudomonal β-lactam LOT for MRSA, MSSA, Streptococcus, and Enterococcus subgroup [1.15 (0.06–2.07) vs. 1.78 (1.28–2.89) days, p = 0.026] were significantly decreased in the post-RDT group. Figure 1: Institutional Use of Vnacomycin ConclusionImplementation of a rapid diagnostic test on gram-positive blood cultures was associated with decreased time to targeted therapy from blood culture collection, time to targeted therapy from positive culture, and vancomycin LOT.Disclosures All Authors: No reported disclosures

239. Outcomes Associated with Empiric Aztreonam Use Compared to Anti-Pseudomonal β-lactams in Patients with Sepsis: An Opportunity for Allergy Stewardship

BackgroundAztreonam is often given to patients with a documented β-lactam allergy in lieu of a first-line anti-pseudomonal β-lactam (APBL). However, aztreonam offers no gram positive coverage and data suggest that gram negative organisms have lower susceptibility rates to this antibiotic than to APBLs. Septic patients are especially vulnerable to poor outcomes since inappropriate initial antimicrobial therapy has been shown to be an independent predictor of increased mortality. The purpose of this study was to determine whether septic patients treated with aztreonam experience inferior outcomes compared to those treated with an APBL.MethodsThis was a retrospective, multicenter, cohort study of all adult patients in metro Charlotte Atrium Health facilities treated for sepsis or septic shock from January 2014 to October 2017. Patients receiving either aztreonam or an APBL were identified using the system-wide sepsis database and enrolled in a 1:2 ratio. Patients were excluded if there was no infection-related discharge ICD-9 or ICD-10 code, if they received both aztreonam and an APBL in the first 8 hours, or if they received fewer than 2 doses of the study antibiotic. The primary endpoint was in-hospital mortality.ResultsA total of 194 patients received aztreonam and 388 patients received an APBL. β-lactam allergies were more common in patients who received aztreonam compared to APBL (97% vs. 14.2%, p < 0.01). In-hospital mortality rates were greater in the patients who received aztreonam vs. APBL (22.7% vs. 12.9%, p = 0.0025). After adjusting for APACHE II score, initial aztreonam exposure remained independently associated with hospital mortality (OR = 1.74, 95% CI: 1.0 – 2.8, p = 0.02). Additionally, we identified an increase in combination therapy with the use of aminoglycosides (28.9% vs. 12.4%, p < 0.0001) and fluoroquinolones (50.5% vs. 25.8%, p < 0.0001) in patients receiving aztreonam. No difference was found in overall length of stay or ICU length of stay.ConclusionIn septic patients, the use of aztreonam as the backbone of antimicrobial therapy may result in increased mortality. This highlights the importance of stewardship interventions that obtain an accurate allergy history and encourage the use of APBL antibiotics whenever feasible.Disclosures Kelly E. Pillinger, PharmD, BCIDP, Pharmacy Times (Other Financial or Material Support, Speaker)

656. Development and Application of a Pragmatic Algorithm for the Detection of Carbapenemase-Producing Pseudomonas aeruginosa (CP-PA)

BackgroundHistorically, carbapenem-resistance in P. aeruginosa (PA) has been mediated by inducible AmpC, drug efflux, and porin loss; however, carbapenemase production is an increasingly recognized entity. Of these mechanisms, carbapenemases can drastically reduce treatment options and rapidly disseminate. Since broad applications of phenotypic (mCIM/eCIM) and PCR-based detection can be labor intensive and costly, we developed an MIC derived algorithm to streamline use of these definitive carbapenemase detection methodologies.MethodsTo develop the testing criteria, a challenge set of PA (n=92), NDM, IMP, VIM, KPC, SPM, GES, cephalosporinase or efflux/porin mutation and wild-type isolates were utilized. Broth microdilution MICs were determined for: ceftazidime (CAZ), cefepime (FEP), piperacillin/tazobactam (TZP), meropenem (MEM), imipenem (IPM), ceftolozane/tazobactam (C/T), and ceftazidime/avibactam (CZA). To assess the utility of CAZ, FEP, TZP, and C/T screening criteria from the challenge set, 1,209 clinical PA isolates from a US surveillance program were tested. Confirmatory genotypic and phenotypic testing for evidence of carbapenemases was conducted on all criteria-derived isolates using the Xpert Carba-R assay and the modified carbapenem inactivation method (mCIM)/EDTA-modified carbapenem inactivation method (eCIM), respectively.ResultsTest performance and characteristics of the challenge set are displayed in Table 1. Of the 1,209 clinical isolates, 230 (19%) were IPM and MEM resistant. 116 isolates met the defined criteria (using most common anti-pseudomonal β-lactams) of: IPM and MEM resistance; non-susceptibility to CAZ, FEP, and TZP. Carba-R identified 5 carbapenemase-producing isolates (all blaVIM-positive), while the mCIM/eCIM detected 7 carbapenemase-producing isolates (including the 5 blaVIM-positive isolates).Table 1. Characteristics of the Challenge Set of 92 P. aeruginosa isolates utilized in algorithm development. ConclusionIn the presence of carbapenem resistance, non-susceptibility to FEP, CAZ, and TZP (or C/T when available) is a useful starting point to delineate CP-PA versus non-CP-PA. This MIC criterion combined with either mCIM/eCIM or PCR-based testing is a pragmatic and streamlined approach to identify CP-PA, while providing vital information to guide therapeutic and infection control measures.Disclosures David P. Nicolau, PharmD, Cepheid (Other Financial or Material Support, Consultant, speaker bureau member or has received research support.)Merck & Co., Inc. (Consultant, Grant/Research Support, Speaker’s Bureau)Wockhardt (Grant/Research Support)

A Critical Evaluation of Newer β-Lactam Antibiotics for Treatment of Pseudomonas aeruginosa Infections.

This article critically evaluates common Pseudomonas aeruginosa resistance mechanisms and the properties newer β-lactam antimicrobials possess to evade these mechanisms. An extensive PubMed, Google Scholar, and ClinicalTrials.gov search was conducted (January 1995 to July 2020) to identify relevant literature on epidemiology, resistance mechanisms, antipseudomonal agents, newer β-lactam agents, and clinical data available pertaining to P aeruginosa. Relevant published articles and package inserts were reviewed for inclusion. Therapeutic options to treat P aeruginosa infections are limited because of its intrinsic and acquired resistance mechanisms. The goal was to identify advances with newer β-lactams and characterize improvements in therapeutic potential for P aeruginosa infections. Multidrug-resistant (MDR) P aeruginosa isolates are increasingly encountered from a variety of infections. This review highlights potential activity gains of newer β-lactam antibacterial drugs and the current clinical data to support their use. Pharmacists will be asked to recommend or evaluate the use of these agents and need to be aware of information specific to P aeruginosa, which differs from experience derived from Enterobacterales infections. Newer agents, including ceftazidime-avibactam, ceftolozane-tazobactam, imipenem-relebactam, and cefiderocol, are useful for the treatment of MDR P aeruginosa infections. These agents offer improved efficacy and less toxicity compared with aminoglycosides and polymyxins and can be used for pathogens that are resistant to first-line antipseudomonal β-lactams. Selection of one agent over another should consider availability, turnaround of susceptibility testing, and product cost. Efficacy data specific for pseudomonal infections are limited, and there are no direct comparisons between the newer agents.

Antibiotic utilization within 18 community hospitals in the United States: A 5-year analysis.

Antibiotic overuse is associated with antibiotic resistance. We evaluated antibiotic utilization defined by days of therapy/1000 patient days (DOT/1000 PD) in various community hospitals across the United States. Community hospitals within the Cardinal Health Drug Cost Opportunity Analytics database were evaluated for the availability of DOT/1000 PD data between 2012 to 2016 for overall and specific antibiotic use and the following classes: narrow-spectrum β-lactams (ampicillin, nafcillin, oxacillin, cefazolin, and cephalexin), non-carbapenem antipseudomonal β-lactams (piperacillin/tazobactam, ceftazidime, and cefepime), carbapenems, anti-methicillin-resistant Staphylococcus aureus agents (vancomycin, linezolid, daptomycin, and tigecycline), and fluoroquinolones. Antibiotic utilization and change in utilization during the study period was calculated using linear regression (β coefficient). Eighteen hospitals had antibiotic utilization data available. Hospitals were primarily urban (72%) with an average of 209 total beds and 22 intensive care unit beds. Mean number of pharmacists in these hospitals was nine with a mean pharmacist: bed ratio of 0.05. While all hospitals had antimicrobial stewardship programs established during the study period, only 78% and 22% had infectious diseases (ID) physician and ID pharmacist on staff, respectively. A decrease in antipseudomonal β-lactams (excluding carbapenems) and fluoroquinolones was observed (β coefficients = -1.2 and -2.6, respectively), all other antibiotic classes had increased utilization. Overall antibiotic utilization increased over 5 years. The increase in narrow-spectrum β-lactams utilization along with the reduction in the use of antipseudomonal β-lactams and fluoroquinolones indicate appropriate antimicrobial stewardship. Institutional antibiotic utilization should be evaluated for appropriateness to limit the overuse of broad-spectrum antibiotics in an effort to reduce resistance development.

Nephrotoxicity of teicoplanin-based combination therapy: focus on piperacillin/tazobactam and other anti-pseudomonal β-lactams.

The concurrent use of vancomycin and piperacillin/tazobactam increases the risk of acute kidney injury (AKI) compared with vancomycin use with other anti-pseudomonal β-lactams (OAPBs). Teicoplanin is a glycopeptide antibiotic with lower nephrotoxicity than that of vancomycin. Whether the concomitant use of teicoplanin and piperacillin/tazobactam also increases the risk of AKI remains unknown. To evaluate the AKI risk between teicoplanin-piperacillin/tazobactam and teicoplanin-OAPBs. This was a retrospective, propensity score-matched cohort study. Adult patients receiving teicoplanin-based combination therapy were included. OAPBs included cefepime, cefoperazone/sulbactam, ceftazidime, doripenem, imipenem/cilastatin and meropenem. Propensity score matching was performed to balance demographic and confounding factors. The primary endpoint was AKI during combination therapy. After propensity score matching, 954 patients (teicoplanin-piperacillin/tazobactam: teicoplanin-OAPBs, 1:3 matched, 243 pairs in total) were included for analysis. The mean age was 66.3 years in the matched cohort and 17.1% of patients had shock. Use of nephrotoxic medications (45.7% versus 48.7%) and baseline renal function (78.88 ± 31.26 versus 81.05 ± 31.53 mL/min/1.73 m2) were similar in the two groups. The median teicoplanin dose was 10.7 mg/kg in both groups. The groups did not differ significantly in terms of AKI risk (14.8% versus 14.2%, P = 0.815). However, the time to AKI appeared shorter in the teicoplanin-piperacillin/tazobactam group (4.64 ± 2.33 versus 6.29 ± 4.72 days, P = 0.039). The combination of teicoplanin and piperacillin/tazobactam was not associated with an increased risk of AKI compared with teicoplanin and OAPBs.

Motivational Application of Standardized Antimicrobial Administration Ratios Within a Healthcare System

Background: Hospitals in the United States have been encouraged to report antimicrobial use (AU) to the CDC NHSN since 2011. Through the NHSN Antimicrobial Use Option module, health systems may compare standardized antimicrobial administration ratios (SAARs) across specific facilities, patient care locations, time periods, and antimicrobial categories. To date, participation in the NHSN Antimicrobial Use Option remains voluntary and the value of reporting antimicrobial use and receiving monthly SAARs to multihospital healthcare systems has not been clearly demonstrated. In this cohort study. we examined potential applications of SAAR within a healthcare system comprising multiple local hospitals. Methods: Three hospitals within Prisma Health-Midlands (hospitals A, B, and C) became participants in the NHSN Antimicrobial Use Option in July 2017. SAAR reports were presented initially in October 2017 and regularly (every 3–4 months) thereafter during interprofessional antimicrobial stewardship system-wide meetings until end of study in June 2019. Through interfacility comparisons and by analyzing SAAR categories in specific patient-care locations, primary healthcare providers and pharmacists were advised to incorporate results into focused antimicrobial stewardship initiatives within their facility. Specific alerts were designed to promote early de-escalation of antipseudomonal β-lactams and vancomycin. The Student t test was used to compare mean SAAR in the preintervention period (July through October 2017) to the postintervention period (November 2017 through June 2019) for all antimicrobials and specific categories and locations within each hospital. Results: During the preintervention period, mean SAAR for all antimicrobials in hospitals A, B, and C were 0.69, 1.09, and 0.60, respectively. Notably, mean SAARs at hospitals A, B, and C in intensive care units (ICU) during the preintervention period were 0.67, 1.36, and 0.83 for broad-spectrum agents used for hospital-onset infections and 0.59, 1.27, and 0.68, respectively, for agents used for resistant gram-positive infections. After antimicrobial stewardship interventions, mean SAARs for all antimicrobials in hospital B decreased from 1.09 to 0.83 in the postintervention period (P &lt; .001). Mean SAARs decreased from 1.36 to 0.81 for broad-spectrum agents used for hospital-onset infections and from 1.27 to 0.72 for agents used for resistant gram-positive infections in ICU at hospital B (P = .03 and P = .01, respectively). No significant changes were noted in hospitals A and C. Conclusions: Reporting AU to the CDC NHSN and the assessment of SAARs across hospitals in a healthcare system had motivational effects on antimicrobial stewardship practices. Enhancement and customization of antimicrobial stewardship interventions was associated with significant and sustained reductions in SAARs for all antimicrobials and specific antimicrobial categories at those locations.Funding: NoneDisclosures: None

Adding Insult to Injury: Mechanistic Basis for How AmpC Mutations Allow Pseudomonas aeruginosa To Accelerate Cephalosporin Hydrolysis and Evade Avibactam.

Pseudomonas aeruginosa is a leading cause of nosocomial infections worldwide and notorious for its broad-spectrum resistance to antibiotics. A key mechanism that provides extensive resistance to β-lactam antibiotics is the inducible expression of AmpC β-lactamase. Recently, a number of clinical isolates expressing mutated forms of AmpC have been found to be clinically resistant to the antipseudomonal β-lactam-β-lactamase inhibitor (BLI) combinations ceftolozane-tazobactam and ceftazidime-avibactam. Here, we compare the enzymatic activity of wild-type (WT) AmpC from PAO1 to those of four of these reported AmpC mutants, bearing mutations E247K (a change of E to K at position 247), G183D, T96I, and ΔG229-E247 (a deletion from position 229 to 247), to gain detailed insights into how these mutations allow the circumvention of these clinically vital antibiotic-inhibitor combinations. We found that these mutations exert a 2-fold effect on the catalytic cycle of AmpC. First, they reduce the stability of the enzyme, thereby increasing its flexibility. This appears to increase the rate of deacylation of the enzyme-bound β-lactam, resulting in greater catalytic efficiencies toward ceftolozane and ceftazidime. Second, these mutations reduce the affinity of avibactam for AmpC by increasing the apparent activation barrier of the enzyme acylation step. This does not influence the catalytic turnover of ceftolozane and ceftazidime significantly, as deacylation is the rate-limiting step for the breakdown of these antibiotic substrates. It is remarkable that these mutations enhance the catalytic efficiency of AmpC toward ceftolozane and ceftazidime while simultaneously reducing susceptibility to inhibition by avibactam. Knowledge gained from the molecular analysis of these and other AmpC resistance mutants will, we believe, aid in the design of β-lactams and BLIs with reduced susceptibility to mutational resistance.

An Evaluation of Treatment Patterns and Associated Outcomes Among Adult Hospitalized Patients With Lower-Risk Community-Acquired Complicated Intra-abdominal Infections: How Often Are Expert Guidelines Followed?

BackgroundExpert guidelines discourage use of antipseudomonal β-lactams and fluoroquinolones in lower-risk patients with community-acquired complicated intra-abdominal infection (CA cIAI). Compliance with these recommendations across US hospitals is unclear. This study sought to determine treatment patterns and associated outcomes among adult hospitalized lower-risk patients with CA cIAI.MethodsA study using data from the Premier Healthcare Database (10/2015–12/2017) was performed. Inclusion criteria: age ≥18 years; hospitalized; had a cIAI at admission; and received antibiotics within the first 4 hospital days. Patients were excluded if they were high risk, were transferred from another health care facility, had a recent hospital admission, or received dialysis within 30 days of admission. Empiric antibiotic treatment patterns and associated outcomes were quantified.ResultsOverall, 46 722 (66%) patients with cIAIs met the lower-risk CA IAI study criteria. Among lower-risk CA IAI patients, the mean (SD) age was 53.4 (18.2) years, and 71% had a Charlson Comorbidity Index score of 0. The most common diagnosis was acute appendicitis with peritonitis (59.7%). Among lower-risk CA IAI patients, 54% received piperacillin/tazobactam, 20% received a fluoroquinolone (FQ), 11% received ceftriaxone, and 7% received ampicillin/sulbactam. Overall, the median hospital length of stay was 4 days and median costs were $12 345 USD. Nearly 90% of patients were discharged home, and <1% died. Outcomes were similar across all empiric treatments received.ConclusionsOveruse of antipseudomonal β-lactams and fluoroquinolones was commonplace among lower-risk CA IAI patients. These findings can serve as the basis for an antimicrobial stewardship initiative in hospitals aspiring to reduce the use of broad-spectrum antibiotics.

Comparison of Ceftriaxone and Antipseudomonal β-Lactam Antibiotics Utilized for Potential AmpC β-Lactamase-Producing Organisms.

Background: Induction of antibiotic resistance is associated with increased morbidity and mortality in AmpC β-lactamase producing Enterobacteriaceae. The use of ceftriaxone is controversial for treatment of these organisms due to concerns for inducible resistance. This study was designed to compare treatment failure rates between ceftriaxone and antipseudomonal β-lactam antibiotics when used as definitive therapy for organisms most commonly associated with chromosomal AmpC β-lactamase production. Methods: A retrospective, single-center cohort study was performed enrolling patients hospitalized with monomicrobial Enterobacter, Citrobacter, or Serratia spp. infections. The primary objective compared proportion of treatment failure between groups. All patients received either ceftriaxone or an antipseudomonal β-lactam alone within 24 hours of culture finalization, and with a duration of at least 72 hours for definitive treatment. Treatment failure was defined as either clinical failure (abnormal white blood cell count or temperature on day 7 or 14 post-antibiotics) or microbiologic failure (regrowth of the same organism at same site within 14 or 21 days). Results: Of 192 total patients, treatment failure was observed in 24/71 patients (34%) receiving ceftriaxone and in 42/121 patients (35%) receiving antipseudomonal β-lactam (P = .98). No difference was observed between clinical or microbiologic failure rates between groups. The ceftriaxone group had significantly more patients undergoing treatment for urinary tract infections (51% vs 17%, P < .001), but treatment failure rates remained similar between groups when comparing infections of all other sources. Conclusion: Ceftriaxone has comparable treatment failure rates to antipseudomonal β-lactams for susceptible Enterobacteriaceae infections and may be considered as a therapeutic option. Further, prospective research is needed to validate optimal dosing and application in all sites of infection.

Efficacy of Antibiotic Combinations against Multidrug-Resistant Pseudomonas aeruginosa in Automated Time-Lapse Microscopy and Static Time-Kill Experiments.

Antibiotic combination therapy is used for severe infections caused by multidrug-resistant (MDR) Gram-negative bacteria, yet data regarding which combinations are most effective are lacking. This study aimed to evaluate the in vitro efficacy of polymyxin B in combination with 13 other antibiotics against four clinical strains of MDR Pseudomonas aeruginosa We evaluated the interactions of polymyxin B in combination with amikacin, aztreonam, cefepime, chloramphenicol, ciprofloxacin, fosfomycin, linezolid, meropenem, minocycline, rifampin, temocillin, thiamphenicol, or trimethoprim by automated time-lapse microscopy using predefined cutoff values indicating inhibition of growth (≤106 CFU/ml) at 24 h. Promising combinations were subsequently evaluated in static time-kill experiments. All strains were intermediate or resistant to polymyxin B, antipseudomonal β-lactams, ciprofloxacin, and amikacin. Genes encoding β-lactamases (e.g., blaPAO and blaOXA-50) and mutations associated with permeability and efflux were detected in all strains. In the time-lapse microscopy experiments, positive interactions were found with 39 of 52 antibiotic combination/bacterial strain setups. Enhanced activity was found against all four strains with polymyxin B used in combination with aztreonam, cefepime, fosfomycin, minocycline, thiamphenicol, and trimethoprim. Time-kill experiments showed additive or synergistic activity with 27 of the 39 tested polymyxin B combinations, most frequently with aztreonam, cefepime, and meropenem. Positive interactions were frequently found with the tested combinations, against strains that harbored several resistance mechanisms to the single drugs, and with antibiotics that are normally not active against P. aeruginosa Further study is needed to explore the clinical utility of these combinations.

Prevalence of Antibiotic-Resistant Pathogens in Culture-Proven Sepsis and Outcomes Associated With Inadequate and Broad-Spectrum Empiric Antibiotic Use

Broad-spectrum antibiotics are recommended for all patients with suspected sepsis to minimize the risk of undertreatment. However, little is known regarding the net prevalence of antibiotic-resistant pathogens across all patients with community-onset sepsis or the outcomes associated with unnecessarily broad empiric treatment. To elucidate the epidemiology of antibiotic-resistant pathogens and the outcomes associated with both undertreatment and overtreatment in patients with culture-positive community-onset sepsis. This cohort study included 17 430 adults admitted to 104 US hospitals between January 2009 and December 2015 with sepsis and positive clinical cultures within 2 days of admission. Data analysis took place from January 2018 to December 2019. Inadequate empiric antibiotic therapy (ie, ≥1 pathogen nonsusceptible to all antibiotics administered on the first or second day of treatment) and unnecessarily broad empiric therapy (ie, active against methicillin-resistant Staphylococcus aureus [MRSA]; vancomycin-resistant Enterococcus [VRE]; ceftriaxone-resistant gram-negative [CTX-RO] organisms, including Pseudomonas aeruginosa; or extended-spectrum β-lactamase [ESBL] gram-negative organisms when none of these were isolated). Prevalence and empiric treatment rates for antibiotic-resistant organisms and associations of inadequate and unnecessarily broad empiric therapy with in-hospital mortality were assessed, adjusting for baseline characteristics and severity of illness. Of 17 430 patients with culture-positive community-onset sepsis (median [interquartile range] age, 69 [57-81] years; 9737 [55.9%] women), 2865 (16.4%) died in the hospital. The most common culture-positive sites were urine (9077 [52.1%]), blood (6968 [40.0%]), and the respiratory tract (2912 [16.7%]). The most common pathogens were Escherichia coli (5873 [33.7%]), S aureus (3706 [21.3%]), and Streptococcus species (2361 [13.5%]). Among 15 183 cases in which all antibiotic-pathogen susceptibility combinations could be calculated, most (12 398 [81.6%]) received adequate empiric antibiotics. Empiric therapy targeted resistant organisms in 11 683 of 17 430 cases (67.0%; primarily vancomycin and anti-Pseudomonal β-lactams), but resistant organisms were uncommon (MRSA, 2045 [11.7%]; CTX-RO, 2278 [13.1%]; VRE, 360 [2.1%]; ESBLs, 133 [0.8%]). The net prevalence for at least 1 resistant gram-positive organism (ie, MRSA or VRE) was 13.6% (2376 patients), and for at least 1 resistant gram-negative organism (ie, CTX-RO, ESBL, or CRE), it was 13.2% (2297 patients). Both inadequate and unnecessarily broad empiric antibiotics were associated with higher mortality after detailed risk adjustment (inadequate empiric antibiotics: odds ratio, 1.19; 95% CI, 1.03-1.37; P = .02; unnecessarily broad empiric antibiotics: odds ratio, 1.22; 95% CI, 1.06-1.40; P = .007). In this study, most patients with community-onset sepsis did not have resistant pathogens, yet broad-spectrum antibiotics were frequently administered. Both inadequate and unnecessarily broad empiric antibiotics were associated with higher mortality. These findings underscore the need for better tests to rapidly identify patients with resistant pathogens and for more judicious use of broad-spectrum antibiotics for empiric sepsis treatment.

Identification of Drug Resistance Determinants in a Clinical Isolate of Pseudomonas aeruginosa by High-Density Transposon Mutagenesis.

With the aim to identify potential new targets to restore antimicrobial susceptibility of multidrug-resistant (MDR) Pseudomonas aeruginosa isolates, we generated a high-density transposon (Tn) insertion mutant library in an MDR P. aeruginosa bloodstream isolate (isolate ID40). The depletion of Tn insertion mutants upon exposure to cefepime or meropenem was measured in order to determine the common resistome for these clinically important antipseudomonal β-lactam antibiotics. The approach was validated by clean deletions of genes involved in peptidoglycan synthesis/recycling, such as the genes for the lytic transglycosylase MltG, the murein (Mur) endopeptidase MepM1, the MurNAc/GlcNAc kinase AmgK, and the uncharacterized protein YgfB, all of which were identified in our screen as playing a decisive role in survival after treatment with cefepime or meropenem. We found that the antibiotic resistance of P. aeruginosa can be overcome by targeting usually nonessential genes that turn essential in the presence of therapeutic concentrations of antibiotics. For all validated genes, we demonstrated that their deletion leads to the reduction of ampC expression, resulting in a significant decrease in β-lactamase activity, and consequently, these mutants partly or completely lost resistance against cephalosporins, carbapenems, and acylaminopenicillins. In summary, the determined resistome may comprise promising targets for the development of drugs that may be used to restore sensitivity to existing antibiotics, specifically in MDR strains of P. aeruginosa.

Attributable nephrotoxicity of vancomycin in critically ill patients: a marginal structural model study.

Although vancomycin nephrotoxicity is recognizable, critically ill patients have other potential reasons for acute kidney injury (AKI) and determining its attributable nephrotoxic risk in this population can be cumbersome. To determine the risk of AKI attributable to vancomycin, controlling for baseline and time-dependent confounders. Time-fixed and daily time-varying variables were extracted from a large public database. The exposures analysed were: (i) IV vancomycin; (ii) serum trough level greater than 15 and 20 mg/L; and (iii) concomitant exposure to vancomycin and piperacillin/tazobactam or other antipseudomonal β-lactams. Censoring and exposure inverse probability of treatment weighting were calculated. Marginal structural models were plotted to evaluate AKI, severe AKI (stage 2/3) and need of renal replacement therapy (RRT). A total of 26 865 patients were included; 19.7% received vancomycin during ICU stay. After adjusting for fixed and time-variable confounders, vancomycin exposure was associated with AKI (HR = 1.24, 95% CI = 1.09-1.38), but not with severe AKI or need of RRT (HR = 1.05, 95% CI = 0.91-1.23 and HR = 0.97, 95% CI = 0.74-1.29, respectively). A serum trough level greater than 20 mg/L was associated with AKI (HR = 1.90, 95% CI = 1.52-2.30) and severe AKI (HR = 1.69, 95% CI = 1.31-2.19), but showed no statistically significant association with need of RRT (HR = 1.48, 95% CI = 0.92-2.56). The vancomycin + piperacillin/tazobactam combination was not associated with a greater risk than vancomycin alone. The attributable nephrotoxicity of vancomycin in critically ill patients is significantly lower than previously suggested and severe AKI is related to vancomycin only when trough serum levels are greater than 20 mg/L.

2253. Comparison of Outcomes Between Patients with and without Cystic Fibrosis Treated with Ceftolozane–Tazobactam for Pseudomonas aeruginosa Infections

BackgroundCeftolozane–tazobactam (C/T) was designed to have enhanced activity against P. aeruginosa and has been shown to retain activity against many isolates that are resistant to other antipseudomonal β-lactams. However, there are no data comparing outcomes in patients with and without cystic fibrosis (CF).MethodsRetrospective, multicenter cohort study conducted at 5 hospitals that included all patients with P. aeruginosa infections who received C/T as definitive therapy between November 2016 and December 2018. The primary outcome at 90 days was a composite of mortality, recurrence, readmission, and inappropriate response at end of therapy (EOT). The secondary outcome was to describe baseline C/T susceptibility and emergence of resistance. All outcomes were adjudicated by 2 infectious diseases specialists.ResultsThirty-five, 27 non-CF and 8 CF, patients were included. CF patients were younger, had greater baseline C/T resistance (50.0% vs. 8.3%, P = 0.02) and were more likely to receive combination therapy. The most common site of infection was pulmonary (71.4%) followed by intra-abdominal (14.3%) and osteomyelitis (5.7%). Overall, 54.3% of patients had an unsuccessful outcome with no difference between CF and non-CF patients (62.5% vs. 51.9%, P = 0.70). There was also no difference between each component of the primary outcome. All 4 CF patients with a baseline-resistant isolate had an appropriate response at EOT, while neither of the 2 non-CF patients did. The C/T MIC distribution in CF and non-CF patients was ≤ 2 μg/mL (0.0%, 64.2%), 4 μg/mL (50.0%, 25%) ≥ 8 μg/mL (50.0%, 8.4%). The median duration of C/T in CF and non-CF patients was 18.5 days (interquartile range [IQR], 14–37.5 days) and 15 days (IQR, 10–25 days). Ten, 7 non-CF and 3 CF, patients had a P. aeruginosa isolate cultured and tested for C/T susceptibility within 90 days of index culture with 80% having an MIC increase. Non-CF patients treated for > 14 days were more likely to have an MIC increase (P = 0.047). All CF patients had an MIC increase.ConclusionWe did not observe a difference in the rate of unsuccessful outcome between CF and non-CF patients; however, our sample size was small. CF patients were more likely to be resistant to C/T at baseline. Resistance emerged frequently in both groups following exposure to C/T.Disclosures All authors: No reported disclosures.

2292. Incidence of Acute Kidney Injury Associated with Duration of Vancomycin and Piperacillin/tazobactam Combination Therapy

BackgroundEmpiric antibiotic therapy for serious and healthcare-acquired infections often requires coverage for resistant pathogens, including methicillin-resistant Staphylococcus aureus (MRSA) and Pseudomonas aeruginosa. These regimens commonly consist of vancomycin plus an antipseudomonal β-lactam. Recent studies have reported increased acute kidney injury (AKI) risk associated with concomitant vancomycin and piperacillin/tazobactam therapy compared with each agent alone. The objective of this study was to determine whether vancomycin with piperacillin/tazobactam had an increased AKI incidence compared with vancomycin plus cefepime or meropenem. Furthermore, data were analyzed to determine whether a specific duration was associated with an increased AKI incidence.MethodsA retrospective cohort study was conducted analyzing patients who received vancomycin in combination with piperacillin/tazobactam (V+PT), cefepime (V+C), or meropenem (V+M) between January 1, 2018 through June 30, 2018. Adult patients with normal baseline renal function and receipt of at least 48 hours of combination therapy, with the two antibiotics initiated within 24 hours of one another, were included. AKI events, evaluated using the Acute Kidney Injury Network (AKIN) criteria, during antibiotic therapy and up to 72 hours after antibiotic discontinuation were recorded. This data were used to calculate the AKI incidence with each regimen and AKI incidence associated with each day of therapy.ResultsA total of 181 patients were included in the study. The incidence of AKI in the V+PT group was 22.8% vs. 5.6% and 16.7% in the V+C and V+M groups, respectively (P = 0.237). Median duration of therapy when AKI occurred was 3 days for V+PT, 4 days for V+C, and 2 days for V+M (P = 0.015). Patients in the V+M group received more nephrotoxic agents compared with V+PT and V+C (P = 0.004). Statistical analysis did not find a specific day of V+PT therapy predictive of AKI. However, a time to event analysis demonstrated a steady increase in AKI risk with V+PT from day 2 through 6.ConclusionAlthough not statistically significant, V+PT therapy was associated with a higher incidence of AKI compared with V+C or V+M. Future studies are needed to further assess the impact of duration of therapy on AKI incidence.Disclosures All authors: No reported disclosures.

1059. Impact of a Syndrome-Based Antimicrobial Stewardship Intervention on Anti-Pseudomonal β-Lactam Use, C. difficile Rates and Cost in an Urban Community Hospital

BackgroundThe use of anti-Pseudomonal β-lactam (APBL) agents has significantly increased in the past decade, carrying higher costs and contributing to antimicrobial pressure. Antimicrobial stewardship (ASP) can promote evidence-based antimicrobial selection and mitigate excess APBL use. We implemented a comprehensive ASP with syndrome-based prospective audit and feedback (PAF) at an urban community hospital. The goal of this study is to assess the impact of syndrome-based PAF on APBL use, C. difficile rates and cost.MethodsASP with all CDC core elements was implemented at a 151-bed community hospital in October 2017. Syndrome-based guidelines and PAF was established and overseen via direct communication with an ID physician. Days of therapy (DOT), cost and C. difficile rates were assessed 12 months before and after ASP. DOT for APBL and non-APBL utilization was tabulated by unit and paired t-test performed.ResultsMost cases reviewed by PAF (51%) were represented in our syndrome-based treatment guidelines (Figure 1). Soft tissue (33%) and intra-abdominal (24%) infections were the most common syndromes. Change to guideline was the most common PAF intervention (62%) followed by de-escalation (30%). At 12 months, total DOT/1,000 increased (392.5 vs. 404) while the proportion of parenteral antimicrobials used decreased (71% vs. 65%). Antibiotic expenditures decreased by 23%, with a reduction in APBL of 20% and non-APBL of 10% (Table 1). Statistically significant reductions APBL use in non-ICU settings (P = 0.0139) and statistically significant increases in non-APBL in ICU settings occurred (P = 0.0001) (Figure 2 and 3). C difficile rates decreased from 21% (3.27 vs. 2.56).ConclusionSyndrome-based PAF was successfully implemented. A reduction in APBL use was seen in non-ICU settings, where evidence-based de-escalation may be more feasible. APBL use remained high in the ICU but was guideline consistent. A rise in non-APBL use also occurred. Certain critical illness syndromes warrant APBLs, but PAF may promote culture-directed and syndrome-specific treatments. ASP increased guideline-based therapy and contributed to decreased broad-spectrum antimicrobial use, antimicrobial expenditures and C difficile rates. Syndrome based PAF can be successfully implemented in community settings. Disclosures All authors: No reported disclosures.

2270. Initial Treatment Selection Among Patients with Recurrent Pseudomonas aeruginosa (PSA) Infections (Infxs): Does Prior PSA Antibiotic Susceptibility Results Effect Subsequent Empiric Treatment Decisions?

BackgroundResistance to commonly used anti-pseudomonal β-lactams (AP-BLs) like piperacillin/tazobactam (TZP), meropenem (MER) and cefepime (CEF) among patients (patients) with PSA infx is increasing. To minimize receipt of DAT among patients with PSA infxs, clinicians need to consider the patient’s risk of having a PSA infx that is NS to commonly used AP-BLs. A well-described risk factor for having a NS AP-BL PSA infx is recent history of an NS AP PSA infx. This study evaluates the likelihood that a patient with a PSA infx receives an AP-BL that was found to be NS on a prior PSA culture.MethodsThis was a multi-center (n = 239), retrospective cohort analysis using the 2018 data from the BD Insights Research Database (Becton, Dickinson and Company). Inclusion criteria: age ≥ 18 years; hospitalized; PSA infx (index PSA infx); occurrence of a PSA infx ≤ 1 year of index PSA infx (post-index PSA infx); and received treatment for the post-index PSA infx for ≥ 24 hours. Frequency of NS to ≥ 1 AP-BL (MER, TZP, or CEF) for the index PSA infxs was calculated. Among patients with an index PSA infx that was NS ≥ 1 AP-BL, the number of patients who received an AP-BL for the post-index PSA infx that was NS on the index PSA infx was determined.ResultsDuring study period, 16,062 patients had a PSA infx and 2,386 (14.9%) of patients had a post-index PsA infx. The most common culture sites for the index and post-index PSA infxs were respiratory and urine. The most commonly prescribed AP-BL for the post-index PSA infx were TZP (41.9%), CEF (40.3%), and MER (30.8%). In total, 1,026 (43%) of patients had an index PSA infx that was NS to ≥1 AP-BL. Among the 1,026 patients with an index PSA infx that was NS to ≥1 AP-BL, 902 (88%) patients received an AP-BL as initial therapy for the post-index PSA infx and 558 (62%) patients received an AP-BL that was reported as NS on the index PSA culture.ConclusionThe findings highlight the importance of considering prior PSA culture and susceptibility data when selecting initial antibiotic therapy for patients who present with a suspected or documented PSA infx and have a history of a prior PSA infx. Patients with history of a PsA infx that was NS to ≥1 AP-BL may benefit from initial use of novel AP-BL therapies.Disclosures All authors: No reported disclosures.