Abstract Background The IDSA 2023 guidance lacks strong evidence about cefiderocol (FDC) efficacy and real-world data are limited. The aim of this study was to evaluate effectiveness, safety, and risk factors for clinical failure (ClinF) associated with FDC use in hospitalized patients. Methods This was a retrospective, observational study. Adults treated with an initial course of FDC for ≥ 48 hours from Feb 2020 - Aug 2023 were included. Primary outcome was clinical success (ClinS) defined as a composite of survival, resolution of signs and symptoms, and absence of both recurrent infection or microbiological failure. Factors associated with success and failure were compared on univariable analysis and those with a p-value < 0.2 and FDC monotherapy were considered for inclusion in a multivariable model for ClinF. Results 87 patients were included. Most common pathogens: Pseudomonas spp (49%), Acinetobacter spp (29%), and Klebsiella spp 16%. Carbapenem-resistance was reported for 93% of isolates and majority of cases were from a respiratory source (72%). At FDC initiation, 39 patients (45%) were admitted to the ICU and the median PITT bacteremia score was 3 (IQR, 1.5-4). ClinS was achieved in 32 patients (37%). Within this composite, 70% survived, 59% resolved their signs/symptoms, 62% had absence of microbiologic failure, and 63% did not recur within 30 days. 16 patients (18%) developed FDC non-susceptibility (NS) within 90 days. ClinS was associated with urine and intra-abdominal sources, while ClinF was associated with COPD, mechanical ventilation, respiratory sources, and higher PITT bacteremia scores. No significant differences found between age, Charlson comorbidity index score, or monotherapy and combination therapy. COPD was found to be an independent factor associated with ClinF [OR 11.5 (95% CI 1.63-82.28, p=0.014)]. Comparing patients who developed FDC NS to those that did not, solid organ transplant [7(44) vs 14(20); p=0.088], longer antibiotic days prior to FDC [14.5 d vs 7 d; p=0.079], and longer FDC duration [14 d vs 10 d; p=0.023] were more common in those that developed NS. Conclusion In this single center experience with mostly respiratory infections, FDC was successfully used with ClinF being associated with underlying illness. The potential development of NS should be further explored. Disclosures All Authors: No reported disclosures

Abstract Background Secondary vancomycin prophylaxis (VP) is one strategy to reduce recurrent C. difficile infection (CDI). Clinical decision support (CDS) was implemented in the electronic health record (Epic®) in 2020 to remind providers about eligibility for VP at time of prescription of broad-spectrum antibiotics in patients with a history of CDI. The effectiveness of this strategy was assessed. CDIFF BPA CDIFF Secondary Prophylaxis Best Practice Alert Methods Retrospective review of an interruptive best practice alert (BPA) for VP at 8 hospitals from 2021-2022. Patients were classified via manual chart review as immunocompetent (immune) or immunocompromised, and were eligible for 3 months and 12 months respectively after an episode of CDI. Demographic characteristics, immune status, receipt of VP, and outcomes (30-day recurrence CDI, death during hospitalization or within 30 days of discharge) were collected. Only the first BPA per patient was included in the demographic and death analysis. Only one alert per hospitalization was included in the VP use and recurrence analysis. Patients with CDI within 10 days prior to the BPA and on the same day as BPA alert were excluded. Descriptive statistics were used to analyze differences. Results Among 616 unique hospitalized patients for whom the BPA was triggered, median age was 64 years; 40% were immune. Approximately 50% were women, with 24% African American and 24% Hispanic. After 1562 BPAs, 13% of immunocompromised and 10% of immune patients were prescribed VP within 24 hours. Median days from previous CDI to BPA was 97 days for immunocompromised and 45 days for immune patients. For immunocompromised patients, frequency of CDI recurrence (11% versus 6%) and frequency of death (14% versus 18%) were not statistically different in the group that got VP and the group that didn’t. Similarly for immune patients, frequency of recurrent CDI (7% versus 8%) or death (16% versus 13%) were not statistically different in the group that got VP and the group that didn’t. Conclusion VP was infrequently initiated despite an interruptive BPA that identified patients with recent history of CDI at the time of prescription of broad-spectrum antibiotics. In this limited sample size, patients had similar outcomes regardless of VP. Further research is needed to understand the barriers for the low uptake, including CDS design and efficacy of VP. Disclosures All Authors: No reported disclosures

Abstract Background There is significant variability in patient serum posaconazole levels, and it is unclear what characteristics increase the risk for subtherapeutic levels. Higher levels have been associated with improved outcomes. The purpose of this study is to identify risk factors associated with subtherapeutic posaconazole serum levels. Methods Retrospective study of adult patients admitted to NewYork-Presbyterian Hospital who received posaconazole with at least one level obtained at steady-state. Levels were obtained after at least five consecutive days of therapy with no interruptions > 24 hours or dosage changes prior to initial level. Patients were grouped based on if the initial level was therapeutic, defined as a serum level > 1 mcg/mL. Risk factor assessment was performed using a logistic regression model. Baseline characteristics between therapeutic and subtherapeutic groups were compared via chi-squared test for categorical variables and independent t-test for continuous variables. Results 383 patients were included: 280 initial levels were therapeutic and 103 were subtherapeutic. Patients primarily consisted of those with solid organ transplant (48.8%) and hematologic malignancy (38.6%). Significant differences between therapeutic and subtherapeutic groups included median weight (73 vs 78 kg, p=0.017) and initial weight-based doses (4.4 vs 4.2 mg/kg, p=0.044), respectively. This prompted an exploratory analysis finding significant association with BMI > 35 (4.1% therapeutic vs 12.1% subtherapeutic, p=0.006). Initial dose thresholds of at least 3 mg/kg and 4 mg/kg showed nonsignificant increases in therapeutic levels (p=0.056 and p=0.107 respectively). On multivariable analysis, subtherapeutic levels were more likely in patients who are black or African American (OR 1.869, 95% CI 1.009, 3.465), had diarrhea (OR 1.978, 95% CI 1.149, 3.408), and had a BMI > 35 (OR 3.538, 95% CI 1.300, 9.628). Conclusion Patients who are Black or African American, have diarrhea, and have a BMI > 35 were identified as having increased risk for subtherapeutic levels at 300 mg daily dosing. Patients at risk may benefit from initial weight-based dosing of at least 4mg/kg, however this requires additional confirmatory studies. Disclosures All Authors: No reported disclosures

Abstract Background Infections caused by Enterobacterales resistant to third generation cephalosporins (Ceph-RE) are rising in incidence. Carbapenems are frequently used to treat Ceph-RE infections based largely on studies of patients with bacteremia. Data evaluating alternative antibiotic options in pneumonia are limited. We assessed outcomes in intensive care unit (ICU) patients with Ceph-RE pneumonia treated with piperacillin-tazobactam (TZP) and cefepime (FEP) versus carbapenems. Methods Adult ICU patients with pneumonia and positive respiratory culture for Ceph-RE between 1/2015-7/2022 were identified from electronic records. The antibiotic given after sensitivity test results and for > 72 hours (h) was termed the definitive agent. Patients who had polymicrobial pneumonia, severe infection at another body site, or were treated for < 72h or with an agent other than a carbapenem, TZP, or FEP were excluded. Nanopore sequencing was used to identify β-lactamase genes (n=68), and TZP and FEP minimum inhibitory concentrations (MIC) were determined by broth microdilution (n=64). The primary outcome was survival to 30 days or hospital discharge. Outcomes were compared in univariable and multivariable analyses. Results Of 81 included patients, 56% were treated with a carbapenem and 44% received TZP or FEP. Patients receiving carbapenems had numerically higher Pitt Bacteremia Scores (PBS) and rates of severe sepsis (Figure 1). 52/68 isolates harbored an extended-spectrum β-lactamase gene; AmpCs were identified in 13 isolates and OXA-1 in 12. The majority of isolates were susceptible to TZP (91%) and FEP (64%). 73% and 92% of patients treated with TZP and FEP, respectively, met the primary outcome versus 67% of carbapenem recipients. In a multivariable model, only severe sepsis/septic shock was an independent predictor of poor outcome (OR 3.1, 95% CI 1.1-9.7, p=0.04); TZP or FEP use trended toward improved survival (OR 0.3, 95% CI 0.1-1.05, p=0.07). Survival did not differ based on the underlying resistance mechanism. Conclusion While ICU patients receiving carbapenems had more severe illness and worse outcomes, TZP and FEP appeared to be effective agents for patients with less severe pneumonia. Alternative therapies are essential to curb ongoing increases in carbapenem resistance. Disclosures Anne-Catrin Uhlemann, MD, PhD, Merck: Grant/Research Support

Abstract Background Carbapenem-resistant Gram-negative infections remain a serious threat due to their increasing incidence and high mortality rates. Since 2015, various antimicrobials with in vitro activity against carbapenem-resistant Enterobacterales (CRE) have been approved for use. There is limited evidence on the safety and efficacy of these novel antimicrobials compared to previous first-line agents, polymyxins, for treating CRE infections. Methods This was a retrospective cohort study that evaluated the clinical efficacy and safety of the novel antimicrobials compared to polymyxin B. Adult patients with a CRE infection treated with ceftazidime-avibactam (CZA), meropenem-vaborbactam (MVB), or polymyxin B (PMB) for at least 2 days between June 2013 to November 2022 were included. Patients receiving the novel agents (CZA+MVB) were compared to PMB. The primary outcome was 30-day mortality. Secondary outcomes included clinical and microbiological success, 90-day recurrence, development of resistance, frequency of acute kidney injury (AKI), and global success. Global success encompassed 30-day mortality, clinical and microbiological success, and 90-day recurrence. Results 110 patients were included: 75 in the novel agents group (53 CZA, 22 MVB) and 35 in the PMB group. The median age was 59 years (IQR 45,70), simplified Pitt bacteremia score (qPITT) was 1 (IQR 1,2), and Charlson Comorbidity score was 4 (IQR 2,6). The most common organism was K. pneumoniae (62%) and the most common site of infection was respiratory (54%) followed by blood (22%). 30-day mortality did not differ between the novel agents compared to PMB (23% vs. 29%; p=0.665). Numerically higher clinical success occurred with the novel agents (72% vs. 54%; p=0.106) while microbiological success was similar (93% vs 91%; p=1.0). In the 18 patients who had follow up positive cultures, 3/9 (33%) developed resistance in the novel agents group compared to 7/9 (78%) in the PMB group. No differences were identified in 90-day recurrence and global success. Patients who received novel agents had less AKI compared to the novel agents (16% vs 54%; p< 0.001). Conclusion Patients receiving CZA and MVB for CRE infections did not have differences in clinical and microbiological outcomes but had less AKI compared to patients receiving PMB. Disclosures All Authors: No reported disclosures

Purpose To share challenges and opportunities for antimicrobial stewardship programs based on one center’s experience during the early weeks of the coronavirus disease 2019 (COVID-19) pandemic. Summary In the spring of 2020, New York City quickly became a hotspot for the COVID-19 pandemic in the United States, putting a strain on local healthcare systems. Antimicrobial stewardship programs faced diagnostic and therapeutic uncertainties as well as healthcare resource challenges. With the lack of effective antivirals, antibiotic use in critically ill patients was difficult to avoid. Uncertainty drove antimicrobial use and thus antimicrobial stewardship principles were paramount. The dramatic influx of patients, drug and equipment shortages, and the need for prescribers to practice in alternative roles only compounded the situation. Establishing enhanced communication, education, and inventory control while leveraging the capabilities of the electronic medical record were some of the tools used to optimize existing resources. Conclusion New York City was a unique and challenging environment during the initial peak of the COVID-19 pandemic. Antimicrobial stewardship programs can learn from each other by sharing lessons learned and practice opportunities to better prepare other programs facing COVID-19 case surges.

BACKGROUND:Patients with COVID-19 may be at increased risk for secondary bacterial infections with MDR pathogens, including carbapenemase-producing Enterobacterales (CPE). OBJECTIVES:We sought to rapidly investigate the clinical characteristics, population structure and mechanisms of resistance of CPE causing secondary infections in patients with COVID-19. METHODS:We retrospectively identified CPE clinical isolates collected from patients testing positive for SARS-CoV-2 between March and April 2020 at our medical centre in New York City. Available isolates underwent nanopore sequencing for rapid genotyping, antibiotic resistance gene detection and phylogenetic analysis. RESULTS:We identified 31 CPE isolates from 13 patients, including 27 Klebsiella pneumoniae and 4 Enterobacter cloacae complex isolates. Most patients (11/13) had a positive respiratory culture and 7/13 developed bacteraemia; treatment failure was common. Twenty isolates were available for WGS. Most K. pneumoniae (16/17) belonged to ST258 and encoded KPC (15 KPC-2; 1 KPC-3); one ST70 isolate encoded KPC-2. E. cloacae isolates belonged to ST270 and encoded NDM-1. Nanopore sequencing enabled identification of at least four distinct ST258 lineages in COVID-19 patients, which were validated by Illumina sequencing data. CONCLUSIONS:While CPE prevalence has declined substantially in New York City in recent years, increased detection in patients with COVID-19 may signal a re-emergence of these highly resistant pathogens in the wake of the global pandemic. Increased surveillance and antimicrobial stewardship efforts, as well as identification of optimal treatment approaches for CPE, will be needed to mitigate their future impact.

Abstract Background Patients hospitalized with coronavirus disease 2019 (COVID-19) are at increased risk of health care–associated infections (HAIs), especially with prolonged hospital stays. We sought to identify incidence, antimicrobial susceptibilities, and outcomes associated with bacterial/fungal secondary infections in a large cohort of patients with COVID-19. Methods We evaluated adult patients diagnosed with COVID-19 between 2 March and 31 May 2020 and hospitalized >24 hours. Data extracted from medical records included diagnoses, vital signs, laboratory results, microbiological data, and antibiotic use. Microbiologically confirmed bacterial and fungal pathogens from clinical cultures were evaluated to characterize community- and health care–associated infections, including describing temporal changes in predominant organisms on presentation and throughout hospitalization. Univariable and multivariable logistic regression analyses were performed to investigate risk factors for HAIs. Results A total of 3028 patients were included and accounted for 899 positive clinical cultures. Overall, 516 (17%) patients with positive cultures met criteria for infection. Community-associated coinfections were identified in 183 (6%) patients, whereas HAIs occurred in 350 (12%) patients. Fifty-seven percent of HAIs were caused by gram-negative bacteria and 19% by fungi. Antibiotic resistance increased with longer hospital stays, with incremental increases in the proportion of vancomycin resistance among enterococci and ceftriaxone and carbapenem resistance among Enterobacterales. Intensive care unit stay, invasive mechanical ventilation, and steroids were associated with HAIs. Conclusions HAIs occur in a small proportion of patients hospitalized with COVID-19 and are most often caused by gram-negative and fungal pathogens. Antibiotic resistance is more prevalent with prolonged hospital stays. Antimicrobial stewardship is imperative in this population to minimize unnecessary broad-spectrum antibiotic use.

Background. The efficacy and safety of methylprednisolone in mechanically ventilated patients with acute respiratory distress syndrome resulting from coronavirus disease 2019 (COVID-19) are unclear. In this study, we evaluated the association between use of methylprednisolone and key clinical outcomes.Methods. Clinical outcomes associated with the use of methylprednisolone were assessed in an unmatched, case-control study; a subset of patients also underwent propensity-score matching. Patients were admitted between 1 March and 12 April, 2020. The primary outcome was ventilator-free days by 28 days after admission. Secondary outcomes included extubation, mortality, discharge, positive cultures, and hyperglycemia.Results. A total of 117 patients met inclusion criteria. Propensity matching yielded a cohort of 42 well-matched pairs. Groups were similar except for hydroxychloroquine and azithromycin use, which were more common in patients who did not receive methylprednisolone. Mean ventilator-free days were significantly higher in patients treated with methylprednisolone (6.21 +/- 7.45 vs 3.14 +/- 6.22; P = .044). The probability of extubation was also increased in patients receiving methylprednisolone (45% vs 21%; P = .021), and there were no significant differences in mortality (19% vs 36%; P = .087). In a multivariable linear regression analysis, only methylprednisolone use was associated with a higher number of ventilator-free days (P = .045). The incidence of positive cultures and hyperglycemia were similar between groups.Conclusions. Methylprednisolone was associated with increased ventilator-free days and higher probability of extubation in a propensity-score matched cohort. Randomized, controlled studies are needed to further define methylprednisolone use in patients with COVID-19.

Abstract Background Patients with COVID-19 may be at increased risk for secondary bacterial infections. At our quaternary care hospital in New York City, the rapid escalation of COVID-19 cases was accompanied by a massive surge in the need for hospital and critical care capacity. During this time, we noted a increase in infections caused by carbapenemase-producing Enterobacterales (CPE). Methods We retrospectively assessed microbiology data to identify patients with positive testing for SARS-CoV-2 who had clinical cultures with meropenem-resistant and/or carbapenemase gene-positive Enterobacterales. We obtained microbiological and clinical data by manual chart review. Available clinical isolates underwent long-range genomic sequencing using the MinION (Oxford) for rapid genotyping, resistance gene detection, and phylogenetic analysis. Results From March 1 to May 18, we identified 33 CPE isolates from 13 patients, including 29 Klebsiella pneumonia and four Enterobacter cloacae. Most patients (11/13) had a positive respiratory culture, and 7/13 developed bacteremia. All patients had prolonged, complex hospitalizations with extensive antibiotic exposure. We performed long-range sequencing on 19 isolates from 12 patients. 15/16 K. pneumoniae isolates belonged to sequence type (ST) 258 encoding KPC (14 KPC-2; 1 KPC-3); one ST70 isolate encoded KPC-2. All four E. cloacae isolates belonged to ST270 and encoded NDM-1. Phylogenetic analysis of ST258 isolates including historical isolates from our hospital revealed a distinct lineage of isolates from COVID-19 patients (72% bootstrap support), with expected clustering of isolates from the same patient and patients that were cohorted together. Conclusion While CPE have declined substantially in New York City in recent years, increased detection in patients with COVID-19 may signal a reemergence of these highly resistant pathogens in the wake of the global pandemic. System-level factors, such as the rapid scale-up of critical care capacity, while clearly needed to address the unprecedented reach of COVID-19, may have contributed to isolate clustering in these patients. Increased surveillance and antimicrobial stewardship efforts will be needed to mitigate the impact of CPE in the future. Disclosures All Authors: No reported disclosures

BACKGROUND:Polymyxins are antimicrobials of last resort for the treatment of carbapenem-resistant Enterobacteriaceae, but resistance in 5% to >40% isolates has been reported. We conducted a genomic survey of clinical polymyxin-resistant (PR) Klebsiella pneumoniae to determine the molecular mechanisms of PR and the role of polymyxin exposure versus transmission in PR emergence. METHODS:We included 88 patients with PR K. pneumoniae from 2011-2018 and collected demographic, antimicrobial exposure, and infection data. Whole-genome sequencing was performed on 388 isolates, including 164 PR isolates. Variant calling and insertion sequence detection were performed, focusing on key genes associated with PR (mgrB, crrAB, phoPQ, and pmrAB). We conducted phylogenetic analyses of key K. pneumoniae multi-locus sequence types (ST258, ST17, ST307, and ST392). RESULTS:Polymyxin exposure was documented in 53/88 (60%) patients prior to PR detection. Through an analysis of key PR genes, we detected 129 individual variants and 72 unique variant combinations in PR isolates. This included multiple, distinct changes in 36% of patients with serial PR isolates. Insertion sequence disruption was limited to mgrB (P < .001). Polymyxin minimum inhibitory concentrations showed stepwise increases with the number of PR genes affected (P < .001). When clusters containing PR isolates in ≥2 patients were analyzed, 10/14 had multiple genetic events leading to PR. CONCLUSIONS:Molecular mechanisms leading to PR in clinical K. pneumoniae isolates are remarkably heterogenous, even within clusters or individual patients. Polymyxin exposure with de novo PR emergence led to PR in the majority of patients, rather than transmission. Optimizing polymyxin use should be a key strategy in stopping the spread of PR.

Abstract Background Pharmacotherapy for carbapenem-resistant Enterobacteriaceae (CRE) infections is limited. There is a paucity of evidence to guide optimal management of CRE infections. Ceftazidime–avibactam, a novel cephalosporin/β-lactamase inhibitor, may be a reasonable alternative to colistin for CRE infections, but data on polymyxin B (PB) are lacking. Given the improved pharmacokinetic profile of PB compared with colistin, we sought to evaluate clinical and microbiological outcomes of patients treated with CAZ-AVI vs. PB for CRE infections. Methods We conducted retrospective cohort study in adult patients treated with CAZ-AVI or PB for a CRE infection between June 2010 and August 2018. The primary outcome was all-cause mortality at 30 days. Secondary outcomes included clinical cure, microbiological cure, and development of resistance. Endpoints were analyzed using standard statistical measures. The influence of clinical variables other than antimicrobial therapy was assessed in a multivariable regression analysis. Results The study included 117 patients, with 42 patients receiving CAZ-AVI and 75 receiving PB. Respiratory and urinary tract infections were most common, occurring in 37.6% and 20.5% of patients, respectively. Bloodstream infections occurred in 45 (35.9%) patients. In the CAZ-AVI group, there were 9 deaths (21.4%), compared with 19 deaths (25.3%) in the PB group (P = 0.653). No statistically significant differences were found in clinical cure or microbiologic cure between CAZ-AVI and PB. PB was associated with a higher incidence of nephrotoxicity (19% vs. 43%; P = 0.048). After adjustment for duration of therapy, combination therapy, and initial WBC, use of PB was not an independent predictor of mortality. Conclusion No statistically significant differences between CAZ-AVI and PB were found in clinical or microbiologic outcomes in this cohort of patients treated for CRE infection. Further studies are necessary to confirm these preliminary findings to optimize clinical practice. Disclosures All authors: No reported disclosures.

Polymyxin B (PB) has reemerged as a common treatment against multidrug-resistant Gram-negative pathogens. However, nephrotoxicity remains a significant dose-limiting side effect, and contemporary pharmacokinetic (PK) data are limited. This study sought to evaluate PB exposure differences in various loading and nonloading strategies according to total body weight (TBW) and adjusted body weight (ABW). Patients treated with PB had plasma samples obtained for clinical care and analyzed using liquid chromatography-tandem mass spectrometry. Compartmental PK models with linear and allometric scaling of TBW were explored. Semiparametric Monte Carlo simulation evaluated the total (i.e., protein bound plus unbound) area under the plasma concentration-time curve (AUCtotal) during the first 24 h of therapy and at 96 h posttherapy for each regimen at the 10th, 50th, and 90th percentiles of TBW and ABW in the derivation cohort. Literature-based values of the 24-h total AUC/MIC ratio (AUC/MICtotal) of ≥50 defined efficacy, and literature-based values of the 72- to 96-h AUCtotal of ≥100 μg · h/ml defined toxicity. Fifty-two patients contributed 156 PB plasma samples. A two-compartment model with allometric scaling of TBW produced a comparable fit (Akaike information criterion [AIC] = 376.7) to that achieved with linear scaling (AIC = 378). The regimen of a loading dose of 2.5 mg/kg of body weight plus a fixed dose of 100 mg every 12 h had the highest probability of achieving a 24-h AUC/MICtotal of ≥50 with the lowest probability of toxicity in all groups at 24 h, aside from those with the lowest 10th percentile of body weight. This is the first study to suggest that a weight-based loading and fixed maintenance (i.e., weight-independent) dosing strategy for polymyxin B may maximize efficacy while balancing toxicity concerns for most patients.

OBJECTIVETo assess antimicrobial prescriber knowledge, attitudes, and practices (KAP) regarding antimicrobial stewardship (AS) and associated barriers to optimal prescribing.DESIGNCross-sectional survey.SETTINGOnline survey.PARTICIPANTSA convenience sample of 2,900 US antimicrobial prescribers at 5 acute-care hospitals within a hospital network.INTERVENTIONThe following characteristics were assessed with an anonymous, online survey in February 2015: attitudes and practices related to antimicrobial resistance, AS programs, and institutional AS resources; antimicrobial prescribing and AS knowledge; and practices and confidence related to antimicrobial prescribing.RESULTSIn total, 402 respondents completed the survey. Knowledge gaps were identified through case-based questions. Some respondents sometimes selected overly broad therapy for the susceptibilities given (29%) and some “usually” or “always” preferred using the most broad-spectrum empiric antimicrobials possible (32%). Nearly all (99%) reported reviewing antimicrobial appropriateness at 48–72 hours, but only 55% reported “always” doing so. Furthermore, 45% of respondents felt that they had not received adequate training regarding antimicrobial prescribing. Some respondents lacked confidence selecting empiric therapy using antibiograms (30%), interpreting susceptibility results (24%), de-escalating therapy (18%), and determining duration of therapy (31%). Postprescription review and feedback (PPRF) was the most commonly cited AS intervention (79%) with potential to improve patient care.CONCLUSIONSBarriers to appropriate antimicrobial selection and de-escalation of antimicrobial therapy were identified among front-line prescribers in acute-care hospitals. Prescribers desired more AS-related education and identified PPRF as the most helpful AS intervention to improve patient care. Educational interventions should be preceded by and tailored to local assessment of educational needs.Infect Control Hosp Epidemiol 2018;39:316–322

ABSTRACT A retrospective study was conducted in hospitalized patients receiving intravenous polymyxin B who underwent therapeutic drug monitoring during treatment. The aim of this study was to assess the population pharmacokinetics (PK) of intravenous polymyxin B in patients with variable total body weights and create a population model for clinical use. Nonlinear mixed-effects modeling analyses were performed. A total of 43 patients were included, and 70% of these patients were male. The median age was 58 years, and the median weight was 78 kg. The median polymyxin B dose was 180 mg/day or 2.8 mg/kg/day. A one-compartment model described the polymyxin B PK well with conditional mean parameter estimates of a clearance (CL) of 2.37 liters/h and a volume of distribution of 34.4 liters and can be employed for clinical population modeling. Total body weight was not significantly associated with CL (Akaike information criterion, 361.6 for the weight-based model versus 359.5 for the non-weight-based model). These data suggest that dosing according to patient body weight requires further exploration. Greater study is needed to assess the relationships between polymyxin B exposures and efficacy and toxicity.

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ABSTRACT In vivo induction of AmpC beta-lactamases produces high-level resistance to many beta-lactam antibiotics in Enterobacteriaceae , often resulting in the need to use carbapenems or cefepime (FEP). The clinical effectiveness of piperacillin-tazobactam (TZP), a weak inducer of AmpC beta-lactamases, is poorly understood. Here, we conducted a case-control study of adult inpatients with bloodstream infections (BSIs) due to Enterobacter , Serratia , or Citrobacter species from 2009 to 2015 to assess outcomes following treatment with TZP compared to FEP or meropenem (MEM). We collected clinical data and screened all isolates for the presence of ampC alleles by PCR. Primary study outcomes were 30-day mortality and persistent bacteremia at ≥72 h from the time of treatment initiation. Of 493 patients with bacteremia, 165 patients met the inclusion criteria, of which 88 were treated with TZP and 77 with FEP or MEM. To minimize differences between covariates, we carried out propensity score matching, which yielded 41 matched pairs. Groups only differed by age, with patients in the TZP group significantly older ( P = 0.012). There were no significant differences in 30-day mortality, persistent bacteremia, 7-day mortality, or treatment escalation between the two treatment groups, including in the propensity score-matched cohort. PCR amplification and sequencing of amp C genes revealed the presence of amp C in isolates with cefoxitin MICs below 16 μg/ml, in particular in Serratia spp., and demonstrated that these alleles were highly genetically diverse. Taken together, TZP may be a valuable treatment option for BSIs due to AmpC beta-lactamase-producing Enterobacteriaceae , diminishing the need for broader-spectrum agents. Future studies are needed to validate these findings.

Background Polymyxins including colistin are an important "last-line" treatment for infections caused by carbapenem-resistant Klebsiella pneumoniae (CRKp). Increasing use of colistin has led to resistance to this cationic antimicrobial peptide. Methods A cohort nested within the Consortium on Resistance against Carbapenems in Klebsiella pneumoniae (CRACKLE) was constructed of patients with infection, or colonization with CRKp isolates tested for colistin susceptibility during the study period of December, 2011 to October, 2014. Reference colistin resistance determination as performed by broth macrodilution was compared to results from clinical microbiology laboratories (Etest) and to polymyxin resistance testing. Each patient was included once, at the time of their first colistin-tested CRKp positive culture. Time to 30-day in-hospital all-cause mortality was evaluated by Kaplan-Meier curves and Cox proportional hazard modeling. Results In 246 patients with CRKp, 13% possessed ColR CRKp. ColR was underestimated by Etest (very major error rate = 35%, major error rate = 0.4%). A variety of rep-PCR strain types were encountered in both the ColS and the ColR groups. Carbapenem resistance was mediated primarily by blaKPC-2 (46%) and blaKPC-3 (50%). ColR was associated with increased hazard for in-hospital mortality (aHR 3.48; 95% confidence interval, 1.73-6.57; P < .001). The plasmid-associated ColR genes, mcr-1 and mcr-2 were not detected in any of the ColR CRKp. Conclusions In this cohort, 13% of patients with CRKp presented with ColR CRKp. The apparent polyclonal nature of the isolates suggests de novo emergence of ColR in this cohort as the primary factor driving ColR. Importantly, mortality was increased in patients with ColR isolates.