Antipseudomonal Β-lactams Research Articles

2264. An Evaluation of Empiric Treatment Patterns for Adult Patients with Community-Onset (CO) “Low-Risk” (LR) Complicated Intra-Abdominal Infections (cIAI) Across US Hospitals

BackgroundCurrent cIAI guidelines recommend that broad-spectrum antibiotics (abs) like anti-pseudomonal β-lactams should be reserved for “high-risk” CO cIAI patients. Fluoroquinolone (FQ) use is also discouraged in geographic areas with a high incidence of FQ-resistance. Compliance with these recommendations are unclear as there are limited data on empiric treatment (tx) patterns for adult patients with cIAI across US hospitals. This study sought to evaluate empiric tx patterns for patients with CO LR cIAI and assess compliance with cIAI guideline recommendations.MethodsA retrospective multi-center study using data from the Premier Research Database (October 2015–December 2017) was performed. Inclusion criteria: age ≥ 18 years; hospitalized; primary cIAI diagnosis and a cIAI surgical procedure or a secondary cIAI diagnosis and cIAI surgical procedure within 5 days of admission; and received an ab within first 4 hospital days. For patients with multiple cIAI admissions, only the first cIAI was considered. Apt was classified as high-risk (HR) if they met any one of the following criteria: sepsis, severe sepsis, septic shock; ≥3 components of sepsis; or ≥2 two physiologic risk factors (age ≥ 70 years, malignancy, kidney dysfunction, hepatic dysfunction, hypoalbuminemia, and significant cardiovascular compromise). Empiric tx was abs received during the first 4 hospital days. Incidence of empiric tx regimen including one of the following abs was determined among LR patients: piperacillin/tazobactam (TZP), meropenem (MER), cefepime (CFP), and FQ.ResultsOverall, 70,275 patients met study criteria; 11,382 (16%) were HR and 58,893 (84%) were LR. Among LR CO cIAI patients, the mean (SD) age was 54.3 (18.1), 52% were male, and the median (IQR) for Charlson Comorbidity Index was 0 (0–1). The most common diagnosis among LR patients was acute appendicitis with peritonitis (53%). The 10 most common empiric antibiotics administered are shown in table. Among LR patients, 52% received TZP, 3% received MER, 3% received CFP, and 20% received a FQ; 8% received ≥2 of these agents.ConclusionOveruse of non-guideline concordant broad-spectrum abs was commonplace among CO cIAI patients classified as LR. These findings can serve as the basis for an antimicrobial stewardship initiative in hospitals aspiring to reduce the use of broad-spectrum antibiotics. Disclosures All authors: No reported disclosures.

192. Augmenting Utility of Rapid Diagnostic Testing in Treatment of Gram-Negative Bacteremia with Stewardship Intervention

BackgroundRapid diagnostic tests (RDT) can identify pathogens in bloodstream infections (BSI) in less than 24 hours. Our institution utilizes an RDT for blood cultures (BCx) that can detect various organisms and resistance determinants. A retrospective evaluation conducted in our institution calculated the negative predictive values (NPV) of various Gram-negative pathogens and susceptibility to target antimicrobials in the absence of detected resistance markers. Resultant NPV >90% for E. coli and K. pneumoniae to ceftriaxone support use of RDT with stewardship intervention for more rapid de-escalation of antimicrobial therapy in patients with resistance marker-negative BSI.MethodsIn our facility, all positive BCx are processed through RDT. In the post-intervention group, pharmacists monitored RDT results and provided recommendations. Our IRB-approved, prospective study assessed time to antimicrobial de-escalation in treatment of resistance marker-negative E. coli and K. pneumoniae BSI before (January 1 to December 31, 2018) and after Stewardship intervention (January 1 to March 31, 2019). Secondary outcomes included days of therapy (DOT) of target narrow-spectrum β-lactams, carbapenems, and non-carbapenem anti-pseudomonal (NCAP) β-lactams, length of stay (LOS), and treatment failure. Data were analyzed using the Fisher exact or Chi-square and t-test for categorical and continuous data, respectively.ResultsOf the 12,893 evaluated RDT results in the pre-intervention group and 2,238 post intervention, 41 and 12 patients met inclusion criteria, respectively. Baseline characteristics were similar in both groups. Time to de-escalation to a target agent was decreased by 24 hours after stewardship intervention (50 v 74.6 hours) (P = 0.14). There were no statistically significant differences in DOTs for target agents (5.19 v 5.25 DOT; P = 0.48), carbapenems (1.29 v 1.08 DOT; P = 0.41), or NCAP β-lactams (1.73 v 2.33; P = 0.25). Treatment failure (2 in each group; P = 0.17) and LOS (10.9 v 11.9 days; P = 0.4) were similar between groups. Protocol compliance and intervention acceptance rate was approximately 60%.ConclusionAppreciation of NPVs and utilization of stewardship intervention allowed for early de-escalation of empiric therapy in patients with resistance marker-negative E. coli and K. pneumoniae bacteremia. Disclosures All authors: No reported disclosures.

1087. Fluoroquinolone Prophylaxis vs. No Bacterial Prophylaxis in Hospitalized Neutropenic Patients Undergoing Induction Chemotherapy for Acute Myeloid Leukemia

BackgroundDespite evidence to support outpatient anti-pseudomonal fluoroquinolone (FQ) prophylaxis in neutropenic patients, limited data exist to support this for inpatients undergoing induction chemotherapy for acute myeloid leukemia (AML). At our institution, we implemented an initiative to replace FQ prophylaxis with a conditional order for an anti-pseudomonal β-lactam to be given if a fever occurred.MethodsA retrospective chart review was conducted to analyze the outcome differences between patients receiving FQ prophylaxis (pre-intervention) and those who had a conditional order for an anti-pseudomonal β-lactam in place of FQ prophylaxis (post-intervention). Patients were included if they were ≥18 years of age and were newly diagnosed with AML undergoing induction chemotherapy. The primary outcome was 90-day all-cause mortality. Secondary outcomes included the number of patients requiring ICU admission and rate of bacteremic episodes caused by any pathogen and from a Gram-negative rod (GNR). Additionally, ciprofloxacin susceptibility of these pathogens was analyzed.ResultsThere were 35 and 26 patients in the pre- and post-intervention groups, respectively. Between pre- and post-intervention groups, there was no difference in 90-day mortality (20.0% vs. 15.4%; P = 0.745) or ICU admissions (25.7% vs. 23.1%, P = 1), respectively. The rate of any bacteremic episode was similar between the pre- and post-intervention groups (51.4% vs. 65.4%; P = 0.307), but more patients in the post-intervention group developed GNR bacteremia (17.1% vs. 46.2%; P = 0.023). In the patients with GNR bacteremia, the number of ciprofloxacin nonsusceptible isolates was higher in the pre-intervention group (100% vs. 30.7%; P = 0.011).ConclusionReplacing FQ prophylaxis with a conditional order for an anti-pseudomonal β-lactam for inpatients newly diagnosed with AML receiving induction chemotherapy is a feasible option to decrease FQ exposure. Though increased episodes of GNR bacteremia were observed, there was no difference in total bacteremic episodes or clinical outcomes, and the improved ciprofloxacin susceptibility patterns will allow for an additional treatment option in this extremely vulnerable patient population. Disclosures All authors: No reported disclosures.

2269. Clinical Outcomes in Patients with Carbapenem-Non-Susceptible, β-Lactam-Susceptible Pseudomonas aeruginosa Infections

Background Pseudomonas aeruginosa (PsAr) isolates harboring OprD mutations often present phenotypically as carbapenem nonsusceptible but susceptible to antipseudomonal β-lactams (APBLs). It is unknown whether this unique genotype–phenotype combination affects the clinical outcomes of patients infected with these pathogens. The objective of this study was to compare clinical outcomes of patients treated with APBLs for pneumonia and/or bacteremia caused by PsAr bearing this unique carbapenem nonsusceptible, β-lactam susceptible phenotype (Carba-NS) to those retaining susceptibility to both carbapenems and APBLs (Carba-S).MethodsRetrospective multicenter cohort of adult in-patients who received effective APBL for PsAr pneumonia and/or bacteremia from January 2012 to November 2018. Baseline characteristics, treatment information, and clinical outcomes were obtained from the electronic medical record. The primary outcome was 14-day mortality. Secondary outcomes included 30-day mortality, 30-day infection recurrence, and infection-related length of stay (IR-LOS). IR-LOS was defined as the time from index culture to antibiotic discontinuation or hospital discharge, whichever was sooner. Descriptive statistics were analyzed using SPSS.Results387 patients were evaluated; 60 Carba-S and 21 Carba-NS were included. The primary reason for exclusion was ineffective empiric therapy. Select demographics and clinical outcomes are displayed in Table 1. Compared with the Carba-S group, Carba-NS patients were younger, had better renal function, increased incidence of pneumonia, more severely ill, and higher rate of empiric ceftazidime use. Despite these differences at baseline there were no significant differences in empiric APBL treatment patterns, 14- or 30-day mortality, or recurrence at 30 days between the groups. Carba-NS patients had lower rate of oral step down therapy and a significantly longer LOS and IR-LOS.ConclusionIn this cohort of patients who received appropriate and timely APBL therapy, the Carba-NS phenotype was not associated with increased rates of 14-day mortality, 30-day mortality, or 30-day infection recurrence. These data suggest that APBLs may be effective therapeutic options against this phenotype. Further research is warranted to confirm these findings. Disclosures All authors: No reported disclosures.

1600. Susceptibility of β-Lactam-Resistant Pseudomonas aeruginosa to Other β-Lactams: Is There Truly a Lack of Cross-Resistance?

BackgroundResistance to β-lactams in P. aeruginosa is complex with multiple mechanisms contributing. Since different mechanisms impact different β-lactams to differing degrees, a common dogma is that resistance to one β-lactam does not lead to resistance to others. The purpose of this analysis was to assess the frequency of β-lactam cross-resistance in P. aeruginosa.MethodsUnique P. aeruginosa isolated in 2017 at Michigan Medicine were included. Overall, susceptibility (using CLSI breakpoints) and MIC distributions of β-lactams were assessed in all isolates and those with β-lactam resistance.Results3,836 unique P. aeruginosa isolates were included. Resistance to traditional anti-pseudomonal β-lactams ranged from 15–23%, whereas ceftolozane/tazobactam resistance was 6%. Overall, cross-resistance between β-lactams was common. The table displays select β-lactam MIC distributions for all isolates and in those resistant to ≥1 β-lactam. When resistance of one agent was present susceptibility to other β-lactams was generally <40% with the majority of susceptible isolates having MICs at or near the breakpoint. Ceftolozane/tazobactam provided the best activity in this setting with 65–77% susceptibility.ConclusionCross-resistance between β-lactams in P. aeruginosa is common. In patients at risk for resistant P. aeruginosa, ceftolozane/tazobactam should be considered for empiric coverage. Disclosures All authors: No reported disclosures.

2278. Emergence of Resistance and Associated Mortality during Persistent Pseudomonas aeruginosa Bacteremia in Hematopoietic Cell Transplant Recipients and Hematologic Malignancy Patients

Background Pseudomonas aeruginosa (PSA) bacteremia causes significant mortality in patients with hematologic malignancies (HM) and hematopoietic cell transplant (HCT) recipients in part due to intrinsic and acquired resistance mechanisms. However, the incidence of developing resistance on therapy and the associated outcomes are poorly described. We characterize the emergence of resistance on therapy and describe the outcomes of PSA bacteremia in this population.MethodsWe conducted a retrospective review of adults with HM and HCT recipients who developed PSA bacteremia between January 2012 and April 2018. A bacteremic episode was characterized as ≤ 14 days from the first positive blood culture. Persistent bacteremia was defined as a positive blood culture ≥ 72 hours of appropriate antibiotic therapy. Susceptibility testing was performed with VITEK2. Isolates were classified as “sensitive,” “intermediate,” or “resistant” per standard criteria; “intermediate” and “resistant” results were considered “non-susceptible.”Results66 episodes of PSA bacteremia occurred in 59 patients. Among episodes in which a patient survived for ≥3 days, 8 (12.1%) met criteria for persistent bacteremia. Non-susceptibility to therapy developed in 5 of 7 episodes (71.4%) of persistent bacteremia; 1 did not have susceptibilities performed on both isolates. Patients with persistent bacteremia had a second positive blood culture within a median of 3.5 days. A concomitant visceral nidus of infection (pneumonia = 6, soft tissue = 1) (P = 0.005) was identified as the primary risk factor for persistent bacteremia. Risk factors for emergence of non-susceptibility could not be determined due low number of events. Infection associated mortality (IAM) (death ≤ 14 days) occurred in 12 (17.1%) of all episodes and 6 of 8 (75%) of persistent bacteremia. Persistent bacteremia was the only risk factor associated with IAM (P = 0.0002, RR 7.3).ConclusionEmergence of resistance to anti-Pseudomonal β-lactam antibiotics frequently occurs during treatment for persistent PSA bacteremia in HCT recipients and HM patients. Persistent bacteremia is associated with a visceral nidus of infection and was the only independent predictor of IAM.Disclosures All authors: No reported disclosures.

Effect of concomitant vancomycin and piperacillin-tazobactam on frequency of acute kidney injury in pediatric patients.

Results of a study of rates of acute kidney injury (AKI) in pediatric patients treated with vancomycin plus piperacillin-tazobactam or vancomycin plus alternative antipseudomonal β-lactams (APBLs) are reported. A retrospective, single-center cohort study was performed. Pediatric patients were included in the study cohort if they received combination therapy for at least 48 hours, had documented baseline and follow-up serum creatinine levels, and had a documented serum vancomycin trough concentration. The primary outcome was the frequency of AKI, defined as a 50% or greater increase in serum creatinine concentration from baseline or an increase of at least 0.5 mg/dL from baseline. The secondary outcome was time to AKI onset. A total of 474 patients were included. Among 100 patients who received vancomycin plus piperacillin-tazobactam, the rate of AKI was higher than the rate in the group treated with vancomycin plus alternative APBLs (27% versus 7%, p < 0.0001). The median time to AKI onset was shorter in the piperacillin-tazobactam group versus the alternative APBL group (3.8 versus 7.9 days, p = 0.0065). Patients who were administered piperacillin-tazobactam were almost 6 times as likely to develop AKI (odds ratio [OR], 5.955; 95% confidence interval [CI], 2.774-12.784), and patients who had a maximum vancomycin trough concentration greater than 20 mg/L were 7.5 times as likely to develop AKI (OR, 7.552; 95% CI, 3.625-15.734). Pediatric patients treated with concomitant vancomycin and piperacillin-tazobactam had a higher rate of AKI, with faster AKI onset, than those who received vancomycin in combination with other APBLs.

Syndrome-specific versus prospective audit and feedback interventions for reducing use of broad-spectrum antimicrobial agents

Antimicrobial use (AU) of antipseudomonal β-lactams (APBL) has significantly increased over the past decade in US hospitals. This retrospective cohort study compares 2 common antimicrobial stewardship strategies, syndrome-specific interventions and antimicrobial postprescription prospective audit and feedback (PAF), in reducing AU of APBL at a large community-teaching hospital. Four antimicrobial stewardship interventions targeting APBL were serially introduced, including 2 syndrome-specific interventions (bloodstream and intra-abdominal infections) and 2 PAF interventions (carbapenems and piperacillin/tazobactam). Multivariable linear regression was used to examine overall AU of APBL and audited antimicrobial agents. Overall AU of APBL declined from 92.4-69.1 days of therapy (DOT) per 1,000 patient-days between February 2013 and July 2017 (P < .001). Both syndrome-specific interventions were associated with significant reduction in AU of APBL (-7.7 [95% confidence interval (CI): -11.5, -4.0] and -6.0 [95% CI: -9.7, -2.3] DOT per 1,000 patient-days) for bloodstream and intra-abdominal infections, respectively). No significant change in overall AU of APBL was observed after implementation of PAF interventions for carbapenems (-1.4 [95% CI: -7.4, 4.6] DOT per 1,000 patient-days) or piperacillin/tazobactam (0.9 [95% CI: -3.7, 5.4] DOT per 1,000 patient-days). Implementation of syndrome-specific interventions was followed by significant reduction in AU of APBL in this population. Despite reducing AU of targeted agents, neither PAF intervention contributed to overall observed decline in APBL use, likely due to compensatory increase in using other APBL.

Selective antibiotic susceptibility reporting and broad-spectrum intravenous antibiotic use: A multicentre ecological study

Recent estimates of inpatient antibiotic use in the USA suggest that broad-spectrum antibiotic use has increased significantly. The objective of this study was to assess the impact of a selective antibiotic susceptibility reporting intervention on broad-spectrum intravenous (i.v.) antibiotic use in seven hospitals of a health system in New Jersey. This was a retrospective pre- and post-intervention ecological study. Standardised selective antibiotic susceptibility reporting rules were developed and implemented between January 2016 and June 2017. The 8 months before and after each individual hospital's implementation constituted the pre- and post-intervention study periods. The primary outcome was the rate of broad-spectrum i.v. antibiotic use for hospital-onset/multidrug-resistant infections (broad MDR). Secondary outcome measures were the use rates of non-glycopeptide anti-methicillin-resistant Staphylococcus aureus (anti-MRSA) agents, carbapenems, non-carbapenem antipseudomonal β-lactams, third-generation cephalosporins, first/second-generation cephalosporins, fluoroquinolones and narrow-spectrum penicillins. Antibiotic use data were collected as inpatient i.v. antibiotic days of therapy per 1000 patient days (DOT/1000-PD). Interrupted time series analysis with segmented regression was used to compare outcomes. There was no significant change in the use of broad MDR agents (slope change, +0.54 DOT/1000-PD per month, 95% confidence interval -1.78 to 2.87) or other antibiotic classes. Whilst the implementation of selective antibiotic susceptibility reporting across seven hospitals had no impact on overall broad-spectrum i.v. antibiotic use, further study is needed to determine the long-term impact of this intervention.

Comparison of the In Vitro Susceptibility of Ceftolozane-Tazobactam With the Cumulative Susceptibility Rates of Standard Antibiotic Combinations When Tested Against Pseudomonas aeruginosa From ICU Patients With Bloodstream Infections or Pneumonia.

Background Pseudomonas aeruginosa remains an important cause of hospital-acquired infections in the United States and is frequently multidrug-resistant (MDR). The Infectious Diseases Society of America guidelines recommend empiric combination therapy that includes an antipseudomonal β-lactam with an aminoglycoside or fluoroquinolone likely to cover ≥95% of P. aeruginosa infections in seriously ill patients at risk of having an MDR pathogen. Ceftolozane is an antipseudomonal cephalosporin, combined with the β-lactamase inhibitor tazobactam. Ceftolozane-tazobactam is approved for treatment of complicated urinary tract infections and complicated intra-abdominal infections. A phase 3 clinical trial for the treatment of hospital-acquired pneumonia including ventilator-associated pneumoniae was recently completed. We compared the in vitro susceptibility rate of ceftolozane-tazobactam with the cumulative susceptibility rates of antibiotic combinations commonly used against P. aeruginosa.MethodsIsolates were collected from intensive care unit patients hospitalized in 32 US hospitals from 2011 to 2017. The susceptibilities of 1543 P. aeruginosa isolates from bloodstream infections (198 isolates, 12.8%) or pneumonia (1345 isolates, 87.2%) were determined for ceftolozane-tazobactam and comparators.ResultsThe most active antimicrobials were colistin (99.4% susceptible), amikacin (98.1% susceptible), and ceftolozane-tazobactam (96.5% susceptible). The susceptibilities to other antipseudomonal β-lactams and fluoroquinolones were <84%. A cumulative susceptibility of ≥95% was reached for cefepime, ceftazidime, meropenem, and piperacillin-tazobactam only in combination with amikacin due to the lower susceptibilities of gentamicin, ciprofloxacin, and levofloxacin. Monotherapies that exceeded 95% were ceftolozane-tazobactam, amikacin, and colistin.ConclusionsCeftolozane-tazobactam monotherapy is likely to be active against more isolates than a combination of another β-lactam and a fluoroquinolone or gentamicin for serious P. aeruginosa infections.

In vitro potency of antipseudomonal β-lactams against blood and respiratory isolates of P. aeruginosa collected from US hospitals.

Challenges due to multidrug resistant (MDR) Gram-negative bacterial pathogens such as P. aeruginosa (PSA) are increasing globally. Suboptimal antimicrobial therapy of infections caused by PSA is associated with increased morbidity and mortality. As a result, antimicrobial susceptibility (%S) studies are pivotal to identifying trends in antimicrobial resistance that inform decisions regarding choice of antimicrobial therapy. This study assessed the in vitro potency of 7 antipseudomonal agents including ceftolozane/tazobactam (C/T) against PSA collected from numerous sites across the US. Multiple US hospitals provided non-duplicate respiratory and blood isolates of PSA for potency testing. MICs against PSA were determined using broth microdilution methods according to CLSI for 7 antimicrobials with antipseudomonal activity: aztreonam (ATM), cefepime (FEP), ceftazidime (CAZ), C/T, imipenem (IPM), meropenem (MEM) and piperacillin/tazobactam (TZP). %S was defined per CLSI or FDA breakpoint criteria. Thirty-five hospitals geographically spread across the US provided a total of 1,209 PSA isolates. Of the antibiotics assessed, %S to C/T was the highest at 95% with an MIC50 of 0.5 mg/L and MIC90 of 2 mg/L. In comparison, other %S (MIC50/MIC90) was as follows: ATM 66% (8/32); FEP 76% (4/32); CAZ 78% (4/64); IPM 68% (2/16); MEM 74% (0.5/16); and TZP 73% (8/128). For this geographically diverse PSA population, C/T demonstrated the highest overall susceptibility (95%). Other antipseudomonal agents inclusive of the carbapenems displayed susceptibilities of 66-78%. In the era of escalating PSA resistance to the β-lactams, the potency of C/T may represent an important clinical option.

Duration of Exposure to Antipseudomonal β-Lactam Antibiotics in the Critically Ill and Development of New Resistance.

Minimizing the duration of broad-spectrum antimicrobial exposure in the critically ill is a commonly used strategy aimed at preventing resistance. Our objective was to correlate the duration of exposure to antipseudomonal β-lactam antibiotics with the development of new resistance in critically ill patients. Single-center, retrospective cohort study. A large, academic, tertiary care hospital. A total of 7118 adults with a discharge diagnosis of severe sepsis or septic shock who received at least one dose of cefepime, meropenem, or piperacillin-tazobactam during their hospitalization between 2010 and 2015. Cohort entry was defined as the first day of any antipseudomonal β-lactam initiation, and exposure was defined as the cumulative days of any antipseudomonal β-lactam exposure during the 60-day follow-up period. The primary outcome was development of new resistance to any antipseudomonal β-lactam > 3 days after cohort entry. New resistance was defined as detection of resistance to any antipseudomonal β-lactam not identified within 180 days before cohort entry. Patients without an outcome (i.e., did not develop new resistance) or who died by day 60 were censored. Cox proportional hazards models were performed to assess the risk of development of new resistance to any antipseudomonal β-lactam with each additional day of exposure. Analyses of each individual antipseudomonal β-lactam were evaluated as secondary outcomes. Each additional day of exposure to any antipseudomonal β-lactam resulted in an adjusted hazard ratio (aHR) of 1.04 (95% confidence interval [CI] 1.04-1.05) for new resistance development. The risk of developing new resistance to cefepime, meropenem, and piperacillin-tazobactam for each additional day of exposure resulted in an aHR of 1.08 (95% CI 1.07-1.09), 1.02 (95% CI 1.01-1.03), and 1.08 (95% CI 1.06-1.09), respectively. Among critically ill patients who receive antipseudomonal β-lactam antibiotics, each additional day of exposure to cefepime, meropenem, and piperacillin-tazobactam is associated with an increased risk of new resistance development.

Impact of De-escalation on Prognosis of Patients With Bacteremia due to Enterobacteriaceae: A Post Hoc Analysis From a Multicenter Prospective Cohort.

More data are needed about the safety of antibiotic de-escalation in specific clinical situations as a strategy to reduce exposure to broad-spectrum antibiotics. The aims of this study were to investigate predictors of de-escalation and its impact on the outcome of patients with bloodstream infection due to Enterobacteriaceae (BSI-E). A post hoc analysis was performed on a prospective, multicenter cohort of patients with BSI-E initially treated with ertapenem or antipseudomonal β-lactams. Logistic regression was used to analyze factors associated with early de-escalation (EDE) and Cox regression for the impact of EDE and late de-escalation (LDE) on 30-day all-cause mortality. A propensity score (PS) for EDE vs no de-escalation (NDE) was calculated. Failure at end of treatment and length of hospital stay were also analyzed. Overall, 516 patients were included. EDE was performed in 241 patients (46%), LDE in 95 (18%), and NDE in 180 (35%). Variables independently associated with a lower probability of EDE were multidrug-resistant isolates (odds ratio [OR], 0.50 [95% confidence interval {CI}, .30-.83]) and nosocomial infection empirically treated with imipenem or meropenem (OR, 0.35 [95% CI, .14-.87]). After controlling for confounders, EDE was not associated with increased risk of mortality; hazard ratios (HR) (95% CIs) were as follows: general model, 0.58 (.25-1.31); model with PS, 0.69 (.29-1.65); and PS-based matched pairs, 0.98 (.76-1.26). LDE was not associated with mortality. De-escalation was not associated with clinical failure or length of hospital stay. De-escalation in patients with monomicrobial bacteremia due to Enterobacteriaceae was not associated with a detrimental impact on clinical outcome.

855. Impact of FDA Black Box Warning on Fluoroquinolone and Alternative Antibiotic Use in Southeastern US Hospitals

BackgroundMany antimicrobial stewardship programs have set goals to reduce the use of fluoroquinolones because of risks of causing C. difficile and other adverse safety events. The US Food and Drug Administration issued a black box label warning for fluoroquinolones in June 2016 recommending avoidance of this class for treatment of uncomplicated infections.MethodsWe performed a retrospective cohort study of antimicrobial use (AU) data in 29 southeastern United States hospitals from 2013 to 2017. An interrupted time series approach with segmented negative binomial regression modeling was used to estimate the longitudinal trend and effect of the FDA safety announcement on AU rates. Fluoroquinolone and alternative antibiotic agent use rates were measured as days of therapy (DOT) per 1,000 patient days. Alternative antibiotics were analyzed individually or in groups (e.g., community-onset agent group included ceftriaxone, cefotaxime, and ertapenem).ResultsHospital AU data for the 60-month period included a total of 6,685,950 patient days; 8 to 29 hospitals contributed AU data to estimates each month. FQ use rates declined at a consistent rate of approximately 1 DOT/1,000 patient days per month resulting in an overall 10% decrease prior to the FDA warning. A significant drop in FQ use rates occurred at the time of the announcement (P = 0.002), but there was no significant change in trend [rate ratio (RR) 0.89, 95% CI 0.79–1.01, P = 0.07, Figure 1]. Alternative antibiotic use significantly increased for the following antibiotic groups after the warning: community-onset agents (RR 1.24, 95% CI 1.11–1.38), atypical agents (RR 1.40, 95% CI 1.19–1.66), and third-generation cephalosporins (RR 1.54, 95% CI 1.19–1.65). Antipseudomonal β-lactam use remained stable (RR 0.96, 95% CI 0.88–1.05, P = 0.3).ConclusionFluoroquinolone use was declining in our network prior to the FDA announcement and continued to decline after 2016. This is likely due to stewardship activities focusing on quinolone-sparing treatment guidelines. AU shifted away from FQ toward third-generation cephalosporins and atypical agents.Figure 1:Figure 2:Disclosures All authors: No reported disclosures.

2138. Impact of De-escalation of Antibiotic Surgical Prophylaxis in Lung Transplant Recipients

BackgroundGuidelines for perioperative antibiotic prophylaxis in lung transplantation (LT) are limited; since Pseudomonas colonization has been linked to acute graft rejection and development of bronchiolitis obliterans syndrome, some centers utilize an anti-pseudomonal β-lactam as part of the surgical prophylaxis regimen. Internal data from our large academic medical center, a center that does not frequently transplant cystic fibrosis patients, identified low rates of Pseudomonascolonization and infection in LT patients. The surgical prophylaxis regimen was therefore narrowed from vancomycin/piperacillin–tazobactam (VPT) in 2013 to vancomycin/ceftriaxone (VCT). The purpose of this study was to examine the protocol change to on the incidence of Pseudomonas isolation in the post-operative period for lung transplant recipients.MethodsThis was a single-center, retrospective quasi-experimental before-after study of lung transplant recipients from July 2006 to February 2017 comparing patients who received VPT to VCT for surgical prophylaxis. Patients receiving other surgical prophylaxis regimens due to allergy or colonization history were excluded. Donor and recipient culture data from bronchoscopy samples were collected to determine the incidence of Pseudomonas in the 14-day post-transplant period. The secondary outcome was the incidence of post-transplant CDC-defined pneumonia. Statistical analysis was performed using SAS 9.4 (Cary, NC).ResultsOne hundred patients were included in the pre-protocol group (VPT), and 65 in the post-protocol group (VCT). Pseudomonas was recovered in recipient BALs on post-op day 2–14 in 8 (8%) patients in the VPT group compared with 5 (7.7%) patients in the VCT group (P = 1.0). Mean time to Pseudomonas isolation was 8.4 days in the VPT group compared with 5.4 days in the VCT group. Incidence of pneumonia on post-op day 2–14 was 6% in the VPT group vs. 3% in the VCT group (P = 0.48). Surgical site infections were rare in the VCT group with an incidence of 1.5% (1/65).ConclusionIsolation of Pseudomonas was rare in both time periods and an increase was not detected when anti-pseudomonal coverage was removed from the surgical prophylaxis regimen. Safe deescalation of surgical prophylaxis regimens are an important antimicrobial stewardship initiative.Disclosures E. Heil, ALK-Abelló: Grant Investigator, Research grant.

Role of Early De-escalation of Antimicrobial Therapy on Risk of Clostridioides difficile Infection Following Enterobacteriaceae Bloodstream Infections

There is a paucity of data on the effect of early de-escalation of antimicrobial therapy on rates of Clostridioides difficile infection (CDI). This retrospective cohort study evaluated impact of de-escalation from antipseudomonal β-lactam (APBL) therapy within 48 hours of Enterobacteriaceae bloodstream infections (BSIs) on 90-day risk of CDI. Adult patients hospitalized for >48 hours for treatment of Enterobacteriaceae BSI at Palmetto Health hospitals in Columbia, South Carolina, from 1 January 2011 through 30 June 2015 were identified. Multivariable Cox proportional hazards regression was used to examine time to CDI in patients who received >48 hours or ≤48 hours of APBL for empirical therapy of Enterobacteriaceae BSI after adjustment for the propensity to receive >48 hours of APBL. Among 808 patients with Enterobacteriaceae BSI, 414 and 394 received >48 and ≤48 hours of APBL, respectively. Incidence of CDI was higher in patients who received >48 hours than those who received ≤48 hours of APBL (7.0% vs 1.8%; log-rank P = .002). After adjustment for propensity to receive >48 hours of APBL and other variables in the multivariable model, receipt of >48 hours of APBL (hazard ratio [HR], 3.56 [95% confidence interval {CI}, 1.48-9.92]; P = .004) and end-stage renal disease (HR, 4.27 [95% CI, 1.89-9.11]; P = .001) were independently associated with higher risk of CDI. The empirical use of APBL for >48 hours was an independent risk factor for CDI. Early de-escalation of APBL using clinical risk assessment tools or rapid diagnostic testing may reduce the incidence of CDI in hospitalized adults with Enterobacteriaceae BSIs.

Incidence of Acute Kidney Injury Among Patients Receiving the Combination of Vancomycin with Piperacillin-Tazobactam or Meropenem.

Vancomycin (VAN) is associated with an increased risk of acute kidney injury (AKI). Evidence is conflicting regarding the risk of AKI when VAN is combined with an antipseudomonal β-lactam. To determine the comparative incidence of AKI when VAN is combined with piperacillin-tazobactam (PTZ) or meropenem (MER). This was a retrospective cohort study of acutely ill adults receiving the combination of VAN and PTZ or MER for at least 48hours between November 1, 2014, and October 31, 2016, in a tertiary care hospital. Critically ill patients and those with baseline renal dysfunction were excluded. The primary outcome was the incidence of AKI during or within 72hours of completing antibiotic therapy, defined as an absolute increase in serum creatinine (Scr ) of 0.5mg/dl or higher or a 50% or more increase in Scr from baseline. Secondary outcomes included time to AKI development, duration of AKI, and length of hospitalization. Continuous variables were assessed using the Wilcoxon rank sum or the Student t test; categorical variables were assessed using χ2 or Fisher exact tests. Independent risk factors for the development of AKI were also examined. A total of 169 patients were evaluated. A significantly higher incidence of AKI was observed in the PTZ group compared with MER (16.5% vs 3.6%; p=0.009). The median time to AKI onset was significantly shorter with PTZ compared with MER (3 vs 7days; p=0.009). After adjusting for baseline differences, VAN/PTZ was associated with a 6.8-fold increased risk of developing AKI (odds ratio [OR] 6.8, 95% confidence interval [CI] 1.5-30.9) compared with VAN/MER. VAN doses higher than 4g/day and trough levels higher than 20μg/ml were independent risk factors for developing AKI (OR 8.7, 95% CI 1.04-72.94, and OR 9.01, 95% CI 1.44-56.21, respectively). The combination of VAN/PTZ increases the risk of AKI when compared with VAN/MER in acutely ill adults.

Fluoroquinolone Prophylaxis Selects for Meropenem-nonsusceptible Pseudomonas aeruginosa in Patients With Hematologic Malignancies and Hematopoietic Cell Transplant Recipients.

In Pseudomonas aeruginosa, fluoroquinolone exposure promotes resistance to carbapenems through upregulation of efflux pumps and transcriptional downregulation of the porin OprD. Evidence of this effect among hematologic malignancy (HM) patients or hematopoietic cell transplant (HCT) recipients receiving fluoroquinolone prophylaxis for neutropenia is lacking. We retrospectively evaluated episodes of P. aeruginosa bloodstream infections in HM patients or HCT recipients over a 7-year period at our institution. We determined the association of fluoroquinolone prophylaxis at the time of infection with meropenem susceptibility of P. aeruginosa breakthrough isolates and risk factors for meropenem nonsusceptibility. Whole-genome sequencing (WGS) and phenotypic assessments of meropenem efflux pump activity were performed on select isolates to determine the mechanisms of meropenem resistance. We analyzed 55 episodes of P. aeruginosa bacteremia among 51 patients. Breakthrough bacteremia while on fluoroquinolone prophylaxis was associated with nonsusceptibility to meropenem, but not to antipseudomonal β-lactams or aminoglycosides. The receipt of fluoroquinolone prophylaxis was independently predictive of bacteremia with a meropenem-nonsusceptible isolate. All meropenem-nonsusceptible isolates analyzed by WGS contained oprD inactivating mutations, and all meropenem-nonsusceptible isolates tested demonstrated reductions in the meropenem minimum inhibitory concentration in the presence of an efflux pump inhibitor. A phylogenetic analysis based on WGS revealed several clusters of closely related isolates from different patients. Fluoroquinolone prophylaxis in HM patients and HCT recipients is associated with breakthrough bacteremia with meropenem-nonsusceptible P. aeruginosa strains, likely due to both mutations increasing efflux pump activity and the epidemiology of P. aeruginosa bloodstream infections in our patient population.

Incidence of Acute Kidney Injury Among Critically Ill Patients With Brief Empiric Use of Antipseudomonal β-Lactams With Vancomycin.

Nephrotoxins contribute to 20%-40% of acute kidney injury (AKI) cases in the intensive care unit (ICU). The combination of piperacillin-tazobactam (PTZ) and vancomycin (VAN) has been identified as nephrotoxic, but existing studies focus on extended durations of therapy rather than the brief empiric courses often used in the ICU. The current study was performed to compare the risk of AKI with a short course of PTZ/VAN to with the risk associated with other antipseudomonal β-lactam/VAN combinations. The study included a retrospective cohort of 3299 ICU patients who received ≥24 but ≤72 hours of an antipseudomonal β-lactam/VAN combination: PTZ/VAN, cefepime (CEF)/VAN, or meropenem (MER)/VAN. The risk of developing stage 2 or 3 AKI was compared between antibiotic groups with multivariable logistic regression adjusted for relevant confounders. We also compared the risk of persistent kidney dysfunction, dialysis dependence, or death at 60 days between groups. The overall incidence of stage 2 or 3 AKI was 9%. Brief exposure to PTZ/VAN did not confer a greater risk of stage 2 or 3 AKI after adjustment for relevant confounders (adjusted odds ratio [95% confidence interval] for PTZ/VAN vs CEF/VAN, 1.11 [.85-1.45]; PTZ/VAN vs MER/VAN, 1.04 [.71-1.42]). No significant differences were noted between groups at 60-day follow-up in the outcomes of persistent kidney dysfunction (P = .08), new dialysis dependence (P = .15), or death (P = .09). Short courses of PTZ/VAN were not associated with a greater risk of short- or 60-day adverse renal outcomes than other empiric broad-spectrum combinations.

Activity of imipenem/relebactam against Pseudomonas aeruginosa with antimicrobial-resistant phenotypes from seven global regions: SMART 2015-2016.

Relebactam inhibits Ambler class A and C β-lactamases. Imipenem/relebactam has completed one phase 3 clinical study of patients infected with imipenem-non-susceptible Gram-negative bacilli. Two more phase 3 clinical studies are in progress for the treatment of patients with hospital-acquired and ventilator-associated bacterial pneumonia, complicated intra-abdominal infections and complicated urinary tract infections. In the current study, clinical Pseudomonas aeruginosa isolates cultured by medical centre laboratories in seven geographic regions (Africa, Asia, Europe, Latin America, Middle East, USA/Canada, South Pacific) were tested for susceptibility to imipenem/relebactam and comparators. A total of 12170 isolates collected as part of the 2015-2016 Study for Monitoring Antimicrobial Resistance Trends (SMART) global surveillance program were tested using the Clinical and Laboratory Standards Institute (CLSI)-defined broth microdilution method. Relebactam was tested at a fixed concentration of 4μg/mL in combination with doubling dilutions of imipenem. Imipenem/relebactam MICs were interpreted using current CLSI breakpoints for imipenem. At the imipenem susceptible breakpoint (≤2μg/mL), imipenem/relebactam inhibited 90.8% of all P. aeruginosa isolates and 70.7% of multidrug-resistant (MDR) isolates (n=3708). Relebactam restored imipenem susceptibility to 70.3% (2656/3776) of imipenem-non-susceptible isolates and increased percent susceptibility to imipenem against isolates with ceftazidime-non-susceptible (by 35.2%), piperacillin/tazobactam-non-susceptible (by 36.6%), cefepime-non-susceptible (by 36.8%) and MDR (by 41.9%) phenotypes. Across the seven geographic regions studied, susceptibility to imipenem/relebactam ranged from 84.0% (Latin America) to 96.0% (South Pacific). Imipenem/relebactam could provide an important treatment option against infections with P. aeruginosa isolates that are non-susceptible to several currently available antipseudomonal β-lactams.