Colistin-associated Stevens-Johnson syndrome and toxic epidermal necrolysis reactions: a retrospective case-non-case pharmacovigilance study

Background: Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are life-threatening skin reactions. Colistin is a last resort antibiotic with a historically poor safety profile. The association between colistin and SJS/TEN has not been previously quantified. Research design and methods: We identified colistin and SJS/TEN adverse event reports from the Food and Drug Administration Adverse Event Reporting System (FAERS) and calculated effect estimates using OpenEpi. Results: From January 2013 through March 2021, 964 adverse events were reported for colistin. Colistin was listed as a secondary suspect drug in 13 SJS/TEN adverse event reports (1.3%), with a reporting odds ratio of 29.6 (95% confidence interval [CI] 17.1–51.1), and proportional reporting ratio of 29.2 (95% CI 17.0–50.2). Limitations of any FAERS study include the voluntary nature of reporting, unclear causal relationship between drug and adverse reaction, underreporting, and wide confidence intervals for rare adverse events like SJS/TEN. Conclusions: Colistin was not the primary suspect drug in any SJS/TEN adverse event reports. We did identify a statistically significant safety signal for SJS/TEN with colistin as a secondary suspect drug. SJS/TEN is not currently included in the colistin product label. This association should be further explored in other pharmacoepidemiologic drug safety studies

1067. Comparative Effectiveness of Nafcillin or Oxacillin, Cefazolin, and Piperacillin/Tazobactam in Methicillin-Sensitive Staphylococcus aureus Bacteremia

Background: β-Lactam antibiotics are recommended as first line for treatment of methicillin-sensitive Staphylococcus aureus (MSSA) bacteremia. The objective of this study was to compare effectiveness among β-lactam therapies in MSSA bacteremia patients that were exclusively treated with one antibiotic. Methods: This was a retrospective cohort study of patients hospitalized at Veterans Affairs (VA) medical centers with MSSA bacteremia from January 1, 2002 to October 1, 2015. Patients were included if they were treated exclusively with nafcillin, oxacillin, cefazolin, or piperacillin/tazobactam (i.e., monotherapy with no changes in therapy). The primary outcome was 30-day mortality, and secondary outcomes were time to discharge, inpatient mortality, 30-day readmission, and 30-day S. aureus reinfection. Hazard ratios (HRs) and 95% confidence intervals (CI) were calculated using unadjusted, quintile adjusted, and propensity-score (PS) matched (nearest neighbor, 0.05 caliper) Cox proportional hazards regression. Results: A total of 326 patients were included in the final analysis. When comparing nafcillin (n = 75)/oxacillin (n = 30) with cefazolin (n = 108), 30-day mortality was similar between groups (PS matched n = 40, HR 4.0, 95% CI 0.45–35.79), as were rates of the other outcomes assessed. When combining nafcillin/oxacillin with cefazolin, and comparing to piperacillin/tazobactam (n = 113), 30-day mortality was significantly lower in the nafcillin/oxacillin/cefazolin group (PS matched n = 66, HR 0.29, 95% CI 0.09–0.87). Inpatient mortality and 30-day mortality were significantly lower with nafcillin/oxacillin/cefazolin in PS-adjusted analyses (HR 0.29, 95% CI 0.11–0.73 and HR 0.23, 95% CI 0.10–0.50, respectively). Conclusion: In hospitalized patients with MSSA bacteremia, no difference in mortality was observed between nafcillin/oxacillin and cefazolin in patients that were exclusively treated with these monotherapies. However, higher mortality was observed with piperacillin/tazobactam as compared with nafcillin/oxacillin/cefazolin, suggesting that it may not be as effective as other monotherapies for MSSA bacteremia

Treatment, Clinical Outcomes, and Predictors of Mortality among a National Cohort of Admitted Patients with Acinetobacter baumannii Infection

The objectives were to analyze treatment, clinical outcomes, and predictors of mortality in hospitalized patients with Acinetobacter baumannii infection. This was a retrospective cohort study of inpatients with A. baumannii cultures and treatment from 2010 to 2019. Patients who died during admission were compared to those who survived, to identify predictors of inpatient mortality, using multivariable unconditional logistic regression models. We identified 4,599 inpatients with A. baumannii infection; 13.6% died during admission. Fluoroquinolones (26.8%), piperacillin-tazobactam (24%), and carbapenems (15.6%) were used for treatment. Tigecycline (3%) and polymyxins (3.7%) were not used often. Predictors of inpatient mortality included current acute respiratory failure (adjusted odds ratio [aOR] 3.94), shock (aOR 3.05), and acute renal failure (aOR 2.01); blood (aOR 1.94) and respiratory (aOR 1.64) infectious source; multidrug-resistant A. baumannii (MDRAB) infection (aOR 1.66); liver disease (aOR 2.15); and inadequate initial treatment (aOR 1.30). Inpatient mortality was higher in those with MDRAB versus non-MDRAB (aOR 1.61) and in those with CRAB versus non-CRAB infection (aOR 1.68). Length of stay \u3e10 days was higher among those with MDRAB versus non-MDRAB (aOR 1.25) and in those with CRAB versus non-CRAB infection (aOR 1.31). In our national cohort of inpatients with A. baumannii infection, clinical outcomes were worse among those with MDRAB and/or CRAB infection. Predictors of inpatient mortality included several current conditions associated with severity, infectious source, underlying illness, and inappropriate treatment. Our study may assist health care providers in the early identification of admitted patients with A. baumannii infection who are at higher risk of death

699. Relationship Between Klebsiella pneumoniae Antimicrobial Resistance and Biofilm Formation

Background: Klebsiella pneumoniae is a frequently multidrug-resistant organism with a high propensity to form biofilm. K. pneumoniae is the most common carbapenem-resistant Enterobacteriaceae (CRE), and labeled an urgent threat by the CDC. The relationship between K. pneumoniae biofilm formation and specific antimicrobial resistance patterns has not been well defined. Methods: K. pneumoniae isolates (n = 139) were evaluated for antimicrobial resistance and biofilm formation (CDC, Providence VA Med. Ctr., Rhode Island Hosp., BEI, and ATCC). Susceptibility was based predominantly on 2017 CLSI (Clinical and Laboratory Standards Institute) breakpoints. Isolates were categorized as multidrug-resistant (MDR: resistant to ≥ 1 antimicrobial in ≥ 3 out of 16 antimicrobial categories) or extensively drug-resistant (XDR: resistant to ≥ 1 antimicrobial in all but ≤ 2 out of 16 antimicrobial categories) based on expert consensus criteria for Enterobacteriaceae (European CDC (ECDC)/CDC, 2012). We collapsed antimicrobial categories described by the ECDC/CDC consensus group into nine categories: penicillins, cephalosporins, monobactam, carbapenems, protein synthesis inhibitors, fluoroquinolones, folate pathway inhibitors, fosfomycin, and colistin. Biofilm formation was assessed using a modified crystal violet method (OD570) and defined by tertile cut-points. Antimicrobial resistance was compared for weak (n = 47) vs. strong (n = 46) biofilm formation by chi-square or Fisher’s exact test. Predictors of strong biofilm formation were identified using logistic regression. Results: MDR isolates were more common among weak (n = 46/47, 97.9%) vs. strong biofilm formers (n = 35/46, 76.1%; P = 0.002), whereas XDR was similar between groups (n = 12/47, 25.5% vs. n = 13/46, 28.3% P = 0.77). Resistance to penicillins, cephalosporins, monobactams, carbapenems, protein synthesis, or fluoroquinolones was more common among weak biofilm formers (P \u3c 0.05). Carbapenem resistance was inversely associated with strong biofilm formation (odds ratio 0.09; 95% confidence interval 0.02–0.33). Conclusion: Carbapenem-resistant K. pneumoniae was 91% less likely to form strong biofilm. Potential trade-off mechanisms between antimicrobial resistance and biofilm formation require further exploratio

Comparative Effectiveness of Exclusive Exposure to Nafcillin or Oxacillin, Cefazolin, Piperacillin/Tazobactam, and Fluoroquinolones Among a National Cohort of Veterans With Methicillin-Susceptible \u3cem\u3eStaphylococcus aureus\u3c/em\u3e Bloodstream Infection

Objective: Beta-lactam antibiotics are recommended as first-line for treatment of methicillin-sensitive Staphylococcus aureus (MSSA) bacteremia. The objective of this study was to compare effectiveness of anti-MSSA therapies among bacteremia patients exclusively exposed to 1 antimicrobial. Method: This was a national retrospective cohort study of patients hospitalized in Veterans Affairs medical centers with MSSA bacteremia from January 1, 2002, to October 1, 2015. Patients were included if they were treated exclusively with nafcillin, oxacillin, cefazolin, piperacillin/tazobactam, or fluoroquinolones (moxifloxacin and levofloxacin). We assessed 30-day mortality, time to discharge, inpatient mortality, 30-day readmission, and 30-day S. aureus reinfection. Hazard ratios (HRs) and 95% confidence intervals (CI) were calculated using propensity-score (PS) matched Cox proportional hazards regression model. Results: When comparing nafcillin/oxacillin (n = 105) with cefazolin (n = 107), 30-day mortality was similar between groups (PS matched n = 44; HR, 0.67; 95% CI, 0.11–4.00), as were rates of the other outcomes assessed. As clinical outcomes did not vary between nafcillin/oxacillin and cefazolin, they were combined for comparison with piperacillin/tazobactam (n = 113) and fluoroquinolones (n = 103). Mortality in the 30 days after culture was significantly lower in the nafcillin/oxacillin/cefazolin group compared with piperacillin/tazobactam (PS matched n = 48; HR, 0.10; 95% CI, 0.01–0.78), and similar when compared with fluoroquinolones (PS matched n = 32; HR, 1.33; 95% CI, 0.30–5.96). Conclusions: In hospitalized patients with MSSA bacteremia, no difference in mortality was observed between nafcillin/oxacillin and cefazolin or fluoroquinolones. However, higher mortality was observed with piperacillin/tazobactam as compared with nafcillin/oxacillin/cefazolin, suggesting it may not be as effective as a monotherapy in MSSA bacteremia

Heterogeneity in the treatment of bloodstream infections identified from antibiotic exposure mapping

Purpose: As changes in antibiotic therapy are common, intent‐to‐treat and definitive therapy exposure definitions in infectious disease clinical trials and observational studies may not accurately reflect all antibiotics received over the course of the infection. Therefore, we sought to describe changes in antibiotic therapy and unique treatment patterns among patients with bacteremia. Methods: We conducted a retrospective cohort study of hospitalizations from Veterans Affairs (VA) Medical Centers (January 2002‐September 2015) and community hospitals (de‐identified Optum Clinformatics DataMart with matched Premier Hospital data; October 2009‐March 2013). In the VA population, antibiotic exposures were mapped from the culture collection date among those with positive Staphylococcus aureus cultures. In the Optum‐Premier population, exposures were mapped from the admission date among those with a primary diagnosis of bacteremia. Results: Our study included 50 467 bacteremia admissions, with only 14% of admissions having the same treatment pattern as another admission. For every 100 bacteremia admissions, 89 had changes in antibiotic therapy. For every 100 bacteremia admissions with changes in therapy, 95 had unique antibiotic treatment patterns. These findings were consistent in both populations, over time, and among different facilities within study populations. The median time to first therapy change was 2 days after initial therapy, with a median of three changes. Conclusions: Changes in antibiotic therapy for bloodstream infections were nearly universal regardless of hospital setting. Based on our findings, common antibiotic exposure definitions of intent‐to‐treat and definitive therapy would misclassify exposure in 86% of admissions, which highlights the need for better operational definitions of exposure in infectious diseases research

Higher Daptomycin Dose Associated with Improved Survival in Methicillin-Resistant Staphylococcus aureus Bacteremia

Study Objective: Current guidelines recommend higher daptomycin doses than the daptomycin label dose of 6 mg/kg for methicillin-resistant Staphylococcus aureus (MRSA) bacteremia; however, the evidence supporting this recommendation is from in vitro and case series studies. This study evaluated the comparative effectiveness of the daptomycin label dose versus higher daptomycin doses in patients with MRSA bacteremia. Design: Retrospective national cohort study. Setting: Veterans Affairs medical centers. Patients: A total of 371 adults with MRSA bacteremia who were admitted between 2002 and 2015 and treated initially with vancomycin within 24 hours of initial culture collection and then switched to daptomycin therapy within 7 days; 138 patients (37.2%) received daptomycin doses higher than the daptomycin label dose (7 mg/kg or greater), and 233 (62.8%) received the daptomycin label dose (6 mg/kg). Measurements and Main Results: Clinical outcomes were compared among those who received the daptomycin label dose and those who received the higher dose using propensity score–matched Cox proportional hazards regression models. To identify dose partitioning associated with optimal survival, classification and regression tree (CART) analysis was used among patients, controlling for confounding with a 30-day mortality disease risk score. Propensity score–matched 30-day mortality was 8.6% (6/70 patients) among the higher dose group versus 18.6% (13/70 patients) among the label dose group (hazard ratio 0.31, 95% confidence interval 0.10–0.94). No significant differences were observed in inpatient mortality, length of stay, 30-day readmission, or 30-day S. aureus reinfection between groups. CART analysis resulted in doses of 7 mg/kg or greater providing benefit only among patients with higher (more than 51%) predicted probabilities of 30-day mortality (p\u3c0.001). Conclusion: To our knowledge, this is the first comparative effectiveness study of daptomycin doses in patients with MRSA bacteremia. Survival benefits were observed with doses higher than the daptomycin label dose (7 mg/kg or greater) for the treatment of MRSA bacteremia. These data suggest that higher doses than the daptomycin label dose may be preferred over the label dose for improving clinical outcomes in patients with MRSA bacteremia

1238. A National Comparison of Antibiograms Between Veterans Affairs Long-Term Care Facilities and Affiliated Hospitals

Background: Long-term care facilities (LTCFs) face several barriers to creating antibiograms. Here, we evaluate if LTCFs can use antibiograms from affiliated hospitals as their own antibiogram. Methods: Facility-specific antibiograms were created for all Veterans Affairs (VA) LTCFs and VA Medical Centers (VAMCs) for 2017. LTCFs and affiliated VAMCs were paired and classified as being on the same campus or geographically distinct campuses based on self-report. For each pair, Escherichia colisusceptibility rates (%S) to cefazolin, ceftriaxone, cefepime, ciprofloxacin, nitrofurantoin, sulfamethoxazole/trimethoprim, ampicillin/sulbactam, piperacillin/tazobactam, and imipenem were compared. As guidelines discourage empiric use of antibiotics if susceptibility rates are Results: A total of 119 LTCFs and their affiliated VAMCs were included in this analysis, with 70.6% (n = 84) of facilities located on the same campus and 29.4% (n = 35) on geographically distinct campuses. The table below shows the overall clinical concordance (agreement) of LTCFs with their affiliated VAMC in regards to E. coli %S to the compared antibiotics. No significant differences were found when comparing LTCFs on the same campus vs. geographically distinct campuses. [Abstract contains a chart of Agreement Rates between LTCFs and Affiliated VAMCs and Antibiotics ] Conclusion: Antibiograms between LTCFs and affiliated VAMCs had a high concordance, except for sulfamethoxazole/trimethoprim, cefazolin and ceftriaxone in regards to susceptibility rates of E. coli. Facilities on the same campus were found to have similar concordance rates to geographically distinct facilities. Future studies are needed to investigate how the various approaches to creating LTCF-specific antibiograms are associated with clinical outcomes

National trends in hospital, long-term care and outpatient Acinetobacter baumannii resistance rates

Introduction: Acinetobacter baumannii is a top-priority pathogen of the World Health Organization (WHO) and the Centers for Disease Control (CDC) due to antibiotic resistance. Gap Statement: Trends in A. baumannii resistance rates that include community isolates are unknown. Aim: Identify trends in A. baumannii resistance rates across the Veterans Affairs (VA) Healthcare System, including isolates from patients treated in hospitals, long-term care facilities and outpatient clinics nationally. Methodology: We included A. baumannii clinical cultures collected from VA patients from 2010 to 2018. Cultures were categorized by location: VA medical centers (VAMCs), long-term care (LTC) units [community living centers (CLCs)], or outpatient. We assessed carbapenem resistance, multidrug resistance (MDR) and extensive drug resistance (XDR). Time trends were assessed with Joinpoint regression. Results: We identified 19 376 A. baumannii cultures (53% VAMCs, 4% CLCs, 43% outpatient). Respiratory cultures were the most common source of carbapenem-resistant (43 %), multidrug-resistant (49 %) and extensively drug-resistant (21 %) isolates. Over the study period, the number of A. baumannii cultures decreased significantly in VAMCs (11.9% per year). In 2018, carbapenem resistance was seen in 28% of VAMC isolates and 36% of CLC isolates, but only 6% of outpatient isolates, while MDR was found in 31% of VAMC isolates and 36% of CLC isolates, but only 8 % of outpatient isolates. Carbapenem-resistant, multidrug-resistant and extensively drug-resistant A. baumannii isolates decreased significantly in VAMCs and outpatient clinics over time (VAMCs: by 4.9, 7.2 and 6.9%; outpatient: by 11.3, 10.5 and 10.2% per year). Resistant phenotypes remained stable in CLCs. Conclusion: In the VA nationally, the prevalence of A. baumannii is decreasing, as is resistance. Carbapenem-resistant and multidrug-resistant A. baumannii remain common in VAMCs and CLCs. The focus of infection control and antimicrobial stewardship efforts to prevent transmission of resistant A. baumannii should be in hospital and LTC settings

Weak biofilm formation among carbapenem-resistant Klebsiella pneumoniae

Biofilm formation of multidrug and extensively drug resistant Klebsiella pneumoniaeisolates is poorly understood. We investigated 139 diverse clinical K. pneumoniaeisolates that possess various resistance patterns to evaluate the relationship between biofilm formation and resistance. Antimicrobial resistance was compared among a diverse collection of weak versus strong biofilm-forming K. pneumoniae, and predictors of strong biofilm formation were identified. Multi-drug resistant isolates were more common among weak (97.9%) versus strong biofilm formers (76%; P = 0.002). Carbapenem-resistant K. pneumoniae were 91% less likely to form strong biofilm (odds ratio 0.09; 95% confidence interval 0.02–0.33). The statistically significant inverse relationship between biofilm formation and antibiotic resistance suggests that virulence may be a trade-off for survival