Abstract Background Beta-lactam allergy (BLA) is associated with increased broad-spectrum antibiotic (Br-ABX) use, worse clinical outcomes, and higher costs. Our hospital-wide BLA protocol (BLA-P) was launched in 7/2021 with following categories: intolerance, low-risk (urticaria only >5 years ago, mild rash, remote childhood reaction with limited details), and high-risk (angioedema, anaphylaxis, severe rashes). Delabeling was done directly based on antibiotic history/interview alone (direct-delabeling), or via graded challenge for low-risk patients. We evaluated the delabeling rate and its impact on Br-ABX usage. Methods Hospitalized patients ≥ 18 years old with listed BLA during 10/2021-12/2022 were eligible. Exclusion criteria were critically ill, surgical, hospice or comfort care, or non-verbal patients. Assessment was counted each time a pharmacist evaluated BLA; multiple assessments could occur in case of prolonged hospital stay or multiple admissions. Interventions were categorized as no further action (due to high-risk allergy, patient refusal for any update, clinical status), updated allergy label, or delabeled. Missed assessments were reported due to logistical issues. Br-ABX usage was compared in the delabeled patients: the empiric antibiotic use 90 days post-intervention versus pre-intervention using McNemar test (SPSS). Results A total of 700 assessments in 631 unique patients with BLA were identified (Figure 1). 556 assessments in 489 unique patients (median age 63 years, 41% male, 46% hematological cancer) met inclusion criteria. In this cohort, the assessments revealed 8% intolerance, 54% low-risk, 17% high-risk and 21% unknown allergy. Interventions resulted in no further action 7%, updated label 72%, and delabeling 21%. 65% of the delabeling was done via direct-delabeling and 35% via graded challenge (Figure 1). Passing rate with graded challenge was 97%. The use of aztreonam and meropenem decreased significantly in delabeled patients compared to pre-delabeling while cefepime and piperacillin-tazobactam usage increased (Table 1). Conclusion Implementation of BLA-P led to 21% delabeling, which resulted in increased use of preferred Br-ABX and a significant decrease in meropenem and aztreonam use. Disclosures Sanjeet S. Dadwal, MD, FACP, FIDSA, Allovir: Advisor/Consultant|Allovir: Grant/Research Support|Ansun Biopharma: Grant/Research Support|Aseptiscope, Inc: Stocks/Bonds|Astellas: Honoraria|Karius: Grant/Research Support|Matinas Biopharma: Stocks/Bonds|Merck: Advisor/Consultant|Merck: Grant/Research Support|Pfizer/Amplyx: Grant/Research Support|Takeda: Advisor/Consultant|Takeda: Honoraria|Viracor: Honoraria Randy Taplitz, MD, Karius: Advisor/Consultant|Merck: Advisor/Consultant|SNIPR biome: Advisor/Consultant

OBJECTIVES/GOALS: In this study, we aim to report the role of porins and blaCTX-M β-lactamases among Escherichia coli and Klebsiella pneumoniae, focusing on emerging carbapenem resistant Enterobacterales (CRE) subtypes, including non-carbapenemase producing Enterobacterales (NCPE) and ertapenem-resistant but meropenem-susceptible (ErMs) strains. METHODS/STUDY POPULATION: Whole genome sequencing was conducted on 76 carbapenem-resistant isolates across 5 hospitals in San Antonio, U.S. Among these, NCP isolates accounted for the majority of CRE (41/76). Identification and antimicrobial susceptibility testing (AST) results were collected from the clinical charts. Repeat speciation was determined through whole genome sequencing (WGS) analysis and repeat AST, performed with microdilution or ETEST®. Minimum inhibitory concentrations (MIC) were consistent with Clinical and Laboratory Standards Institute (CLSI M100, ED33). WGS and qPCR were used to characterize the resistome of all clinical CRE subtypes, while western blotting and liquid chromatography with tandem mass spectrometry (LC-MS-MS) were used to determine porin expression and carbapenem hydrolysis, respectively. RESULTS/ANTICIPATED RESULTS: blaCTX-Mwas found to be most prevalent among NCP isolates (p = 0.02). LC-MS/MS analysis of carbapenem hydrolysis revealed that blaCTX-M-mediated carbapenem hydrolysis, indicating the need to reappraise the term, “non-carbapenemase (NCP)®” for quantitatively uncharacterized CRE strains harboring blaCTX-M. Susceptibility results showed that 56% of all NCPE isolates had an ErMs phenotype (NCPE vs. CPE, p < 0.001), with E. coli driving the phenotype (E. coli vs. K. pneumoniae, p < 0.001). ErMs strains carrying blaCTX-M, had 4-fold more copies of blaCTX-M than ceftriaxone-resistant but ertapenem-susceptible isolates (3.7 v. 0.9, p < 0.001). Immunoblot analysis demonstrated the absence of OmpC expression in NCP-ErMs E. coli, with 92% of strains lacking full contig coverage ofompC. DISCUSSION/SIGNIFICANCE: Overall, this work provides evidence of a collaborative effort between blaCTX-M and OmpC in NCP strains that confer resistance to ertapenem but not meropenem. Clinically, CRE subtypes are not readily appreciated, potentially leading to mismanagement of CRE infected patients. A greater focus on optimal treatments for CRE subtypes is needed.

Among carbapenem-resistant Enterobacterales (CRE) are diverse mechanisms, including those that are resistant to meropenem but susceptible to ertapenem, adding further complexity to the clinical landscape. This study investigates the emergence of ertapenem-resistant, meropenem-susceptible (ErMs) Escherichia coli and Klebsiella pneumoniae CRE across five hospitals in San Antonio, Texas, USA, from 2012 to 2018. The majority of the CRE isolates were non-carbapenemase producers (NCP; 54%; 41/76); 56% of all NCP isolates had an ErMs phenotype. Among ErMs strains, E. coli comprised the majority (72%). ErMs strains carrying blaCTX-M had, on average, 9-fold higher copies of blaCTX-M than CP-ErMs strains as well as approximately 4-fold more copies than blaCTX-M-positive but ertapenem- and meropenem-susceptible (EsMs) strains (3.7 vs. 0.9, p < 0.001). Notably, carbapenem hydrolysis was observed to be mediated by strains harboring blaCTX-M with and without a carbapenemase(s). ErMs also carried more mobile genetic elements, particularly IS26 composite transposons, than EsMs (37 vs. 0.2, p < 0.0001). MGE- ISVsa5 was uniquely more abundant in ErMs than either EsMs or ErMr strains, with over 30 more average ISVsa5 counts than both phenotype groups (p < 0.0001). Immunoblot analysis demonstrated the absence of OmpC expression in NCP-ErMs E. coli, with 92% of strains lacking full contig coverage of ompC. Overall, our findings characterize both collaborative and independent efforts between blaCTX-M and OmpC in ErMs strains, indicating the need to reappraise the term "non-carbapenemase (NCP)", particularly for strains highly expressing blaCTX-M. To improve outcomes for CRE-infected patients, future efforts should focus on mechanisms underlying the emerging ErMs subphenotype of CRE strains to develop technologies for its rapid detection and provide targeted therapeutic strategies.

We reviewed the epidemiology, risk factors, pathophysiology, and clinical presentations of coronavirus disease 2019 (COVID-19)-associated mucormycosis (CAM), then discussed the importance of rapid diagnosis and treatment facilitated by multidisciplinary approach. India has reported world’s highest number of CAM cases where Rhizopus arrhizus was the most predominant etiology. CAM caused by Rhizopus microsporus was the most common from the rest of the world. Multiple risk factors for CAM were identified including diabetes mellitus, inappropriate corticosteroid use, COVID-19-related hypoxia, and lung damage. Rhino-orbito-cerebral mucormycosis (ROCM) accounted for almost 90% of CAM in India while 64% of global cases were ROCM. Less than 10% of CAM from India were pulmonary while the rest of the world reported 21% of pulmonary CAM. CAM is diagnosed by confirmed SARS-CoV2 infection along with clinical, radiological, histopathological, and/or microbiological evidence of mucormycosis. In patients with risks of CAM and associated symptoms, CT or MRI are recommended. If ROCM is suspected, endoscopy and biopsy are recommended. If pulmonary CAM is suspected, tissue biopsies, nasal samples, or bronchoalveolar lavage is recommended with histopathological exams. Early diagnosis, surgical, and pharmaceutical interventions are key to treat mucormycosis. Upon diagnosis, antifungal therapy with liposomal amphotericin B (IV) is considered first-line of therapy. Alternatively, posaconazole (PO/IV) or isavuconazole (PO/IV) can be used. Treating CAM requires a multidisciplinary approach for early diagnosis and prompt initiation of interventions to maximize patient’s chance of survival.

We examined the characteristics of pro-calcitonin (PCT) in hospitalized COVID-19 patients (cohort 1) and clinical outcomes of antibiotic use stratified by PCT in non-critically ill patients without bacterial co-infection (cohort 2). Retrospective reviews were performed in adult, hospitalized COVID-19 patients during March–May 2020. For cohort 1, we excluded hospital transfers, renal disease and extra-pulmonary infection without isolated pathogen(s). For cohort 2, we further excluded microbiologically confirmed infection, ‘do not resuscitate ± do not intubate’ status, and intensive care unit (ICU). For cohort 1, PCT was compared between absent/low-suspicion and proven bacterial co-infections. Factors associated with elevated PCT and sensitivity/specificity/PPV/NPV of PCT cutoffs for identifying bacterial co-infections were explored. For cohort 2, clinical outcomes including mechanical ventilation within 5 days (MV5) were compared between the antibiotic and non-antibiotic groups stratified by PCT ≥ 0.25 µg/L. Nine hundred and twenty four non-ICU and 103 ICU patients were included (cohort 1). The median PCT was higher in proven vs. absent/low-suspicion of bacterial co-infection. Elevated PCT was significantly associated with proven bacterial co-infection, ICU status and oxygen requirement. For PCT ≥ 0.25 µg/L, sensitivity/specificity/PPV/NPV were 69/65/6.5/98% (non-ICU) and 75/33/8.6/94% (ICU). For cohort 2, 756/1305 (58%) patients were included. Baseline characteristics were balanced between the antibiotic and non-antibiotic groups except PCT ≥ 0.25 µg/L (antibiotic:non-antibiotic = 59%:24%) and tocilizumab use (antibiotic:non-antibiotic = 5%:2%). 23% (PCT < 0.25 µg/L) and 58% (PCT ≥ 0.25 µg/L) received antibiotics. Antibiotic group had significantly higher rates of MV5. COVID-19 severity inferred from ICU status and oxygen requirement as well as the presence of bacterial co-infections were associated with elevated PCT. PCT showed poor PPV and high NPV for proven bacterial co-infections. The use of antibiotics did not show improved clinical outcomes in COVID-19 patients with PCT ≥ 0.25 µg/L outside of ICU when bacterial co-infections are of low suspicion.

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.

Abstract Background Carbapenem-resistant Enterobacterales are a growing threat globally. Early detection of CRE is necessary for appropriate treatment and infection control measures. Many hospital labs can test for carbapenemase production; however, in some regions, including South Texas, the majority of CRE are non-carbapenemase producing (NCPE). This study had two interrelated aims to develop decision rules tailored to a region with high prevalence of NCPE to predict 1) antimicrobial resistance (AMR) from whole genome sequencing (WGS) data and 2) CRE treatment outcomes. Methods To better understand links between resistome, phenotypic AMR, and prediction of outcomes for CRE, we developed decision rules to build machine learning prediction models. We conducted WGS and antibiotic susceptibility testing (21 antibiotics) on CRE isolates from unique patients across 5 hospitals in the South Texas region between 2013 and 2020. Day 30 outcomes were based on desirability of outcome ranking (DOOR). The overall classification accuracies of the models are reported. Results Overall 146 CRE isolates were included, 97 were used to train each model, and 49 were used for validation. Among the K. pneumoniae and E. coli CRE isolates that were available with susceptibility data, the majority (62%) were NCPE. For the clinical recovery model (DOOR), the combination of admission ICU status, piperacillin-tazobactam (PT) MIC &gt; 16, presence of sul gene, and polymyxin-sparring regimens associated with an overall accuracy of 95% for having a worse DOOR. Majority (60%) of patients were empirically treated with piperacillin-tazobactam; notably, less than 33% isolates had PT MIC ≤ 16. Interestingly, combined effects of isolates that did not harbor carbapenemases, blaOXA-1, blaCTX-M-15, blaCMY, or aac(6’)ib-cr genes resulted in a decision rule with a 95.7% overall accuracy for susceptibility to PT (MIC &lt; 16 ug/mL). Conclusion Herein, we used machine learning approaches to predict AMR and treatment-based outcomes linked with WGS data in a region with predominantly NCPE infections. Machine learning can obtain a model that can make repeatable predictions, further data can improve the accuracy and guide tailored clinical decision-making. Disclosures Grace Lee, PharmD, PhD, BCPS, Merck Co. (Grant/Research Support)NIA/NIH (Research Grant or Support)

Background Carbapenem-resistant Enterobacterales (CRE) pose a significant global public health threat. Resistance among CRE is particularly complex, owing to numerous possible resistance mechanisms and broad definitions. We aimed to characterize the clinical and molecular profiles of CRE in the South Texas region. Materials and methods We compared the clinical, genotypic, and phenotypic profiles of carbapenemase producing Enterobacterales (CPE) with those of non-carbapenemase producers (NCPE) isolated from South Texas, United States between 2011 and 2019. Molecular characteristics and resistance mechanisms were analyzed using whole-genome sequences. Results The majority (59%) of the CRE isolates were NCPE while 41% of isolates harbored carbapenemases, predmonantly blaKPC-type. The most common CPE was Klebsiella pneumoniae while majority of Enterobacter cloacae and Escherichia coli were NCPE Among K. pneumoniae, the clonal group 307 has emerged as a predmoninant group and was associated with as many CRE infections as the previous common clonal group 258. Patients with NCPE compared to CPE infections were associated with higher antimicrobial exposure prior to culture collection (days of therapy, 795 vs. 242; p < 0.001) and emergency department visits within past 90 days (22% vs. 4%; p = 0.011). The all cause 30-day mortality was 21%. Conclusions This study highlights the diversity of resistance mechanisms underlying CRE in South Texas, with 59% not harboring a carbapenemase. Individuals with NCPE infections were more likely to have had prior antimicrobial therapy and emergency department visits compared to those with CPE. Identification and distinction of these mechanisms by rapid identification of species and carbapenemase would allow for optimal treatment and infection control efforts.

A risk mitigation strategy was implemented to determine if a higher prophylactic voriconazole dosage in patients with CYP2C19 rapid metabolizer neutropenic acute myeloid leukemia (AML) reduces the incidence of subtherapeutic trough concentrations. Patients with AML ( n = 263) were preemptively genotyped for CYP2C19*2 , *3 , and *17 alleles as part of a single‐center prospective, interventional, quality improvement study. CYP2C19 rapid metabolizers ( CYP2C19*1/*17 ) were recommended to receive interventional voriconazole 300 mg twice daily, ultrarapid metabolizers ( CYP2C19*17/*17 ) were recommended to avoid voriconazole, and all others received the standard prophylactic dosage of 200 mg twice daily. In this real‐world setting, 202 patients (76.8%) were prescribed prophylactic voriconazole, and of these patients 176 (87.1%) received CYP2C19 ‐guided prophylactic dosing. Voriconazole trough concentrations were obtained for 41 of the 58 (70.7%) CYP2C19 rapid metabolizers prescribed prophylactic voriconazole. Interventional voriconazole resulted in higher plasma trough concentrations (median 2.7 μg/mL) compared with the standard prophylactic dosage (median 0.6 μg/mL; P = 0.001). Subtherapeutic concentrations were avoided in 83.8% of CYP2C19 rapid metabolizers receiving interventional dosage compared to 46.2% receiving standard dosage ( P = 0.02). CYP2C19 genotyping to preemptively guide prophylactic voriconazole dosing is feasible and may be a potential strategy for reducing the risk of subtherapeutic trough concentrations that potentiate breakthrough fungal infections.

Abstract Background Ceftolozane/tazobactam (CT) is a cephalosporin/β-lactamase inhibitor with excellent activity against multi-drug-resistant (MDR) P. aeruginosa (PSA). Several cases of CT-resistance (CT-R) development after exposure have been reported. We recovered a PSA isolate with high-level CT-R from a bacteremic patient with severe, prolonged neutropenia and 5 weeks of CT exposure. Then, multiple mutational pathways and the role of combination therapy were evaluated. Methods Minimum inhibitory concentrations (MIC) to CT were determined by Etest. Synergy tests between CT and tobramycin (TOB) were conducted and interpreted based on the fractional inhibitory concentration index (FICI). Furthermore, whole genome sequencing was performed. Paired-end reads were mapped and compared with reference strain PAO1. Variant analyses were conducted using CLC Genomics Workbench. Results The MICs for CT and TOB were >256 and 4 mg/L, respectively. The combination revealed synergistic effects (FICI < 0.5) with reduced CT and TOB MICs to 16 and 1 mg/L, respectively. Clinically, combination therapy of CT 3g q8h given over 4 hours and TOB 7 mg/kg q24h successfully cleared the bacteremia within 2 days. Genomic analysis revealed the CT-R isolate contained multiple variants in the ampC gene, including G183D associated with low level CT-R. Two additional variants in aminoacid position 79 (R79Q) and position 105 (T105A) were located inside or near helix-H2 which interacts with the Ω-loop through hydrogen-binding rendering the serine active site more pliable to accommodate larger molecules. Moreover, the CT-R isolate showed a truncated ampD and multiple mutations in mexD, mexT, mexI, and mexR, a primary regulator of mexAB-oprM. The isolate also contained the oprD mutation (Q142X) and an oprD-inactivating mutation (W417X). In addition to these chromosomal mutations, the isolate harbored OXA-50, blaPAO1, and aph(3′)-IIb. Conclusion High-level CT-R was likely driven by multiple mutations in the ampC region causing structural changes. While resistance to CT is worrisome, our case of a severe neutropenic patient who rapidly cleared bacteremia on CT 3g qh8 given over 4 hours plus TOB emphasizes the importance of strategic combination and dosing in combating MDR PSA. Disclosures All authors: No reported disclosures.

Background Blinatumomab is an anti-CD19 immunotherapy approved for relapsed/refractory B-cell acute lymphoblastic leukemia (ALL) with significantly increased survival rate. While blinatumomab showed lower rates of infection, neutropenia and mucosal barrier injury versus chemotherapy, its infection risks are not well described. Methods All patients who received blinatumomab for ≥ seven days at an academic cancer center from May 2015 to April 2017 were included. Patient characteristics pertinent to infectious risks and complications were examined. Results Twenty patients with refractory (25%), relapsed (70%), or remitted (5%) B-ALL who received a total of 35 cycles were included. Ten of the 35 cycles were interrupted, none of which were due to infections. Twenty-six infections (n) were observed with lower respiratory (9), gastrointestinal (6) and bacteremia (5) being most common. Compared to patients without nodular, possible mold pneumonia (n=16), patients with nodular pneumonia (n=4) had significantly lower baseline absolute neutrophil count (ANC) (2319 v. 208/μL, p=0.011). There were no differences in baseline characteristics including ANC between bacteremic and non-bacteremic patients. One patient was discharged with no antibacterial prophylaxis since ANC recovered to >500cells/μL, but developed Pseudomonal bacteremia within a week with ANC ~100cells/μL. Conclusion Despite blinatumomab’s relatively modest myelosuppression and the lack of mucotoxicity, host factors (e.g., duration and degree of neutropenia/lymphopenia) play a key role and should be considered when choosing anti-microbial prophylaxis. In relapsed/refractory disease, the ANC should be monitored closely post blinatumomab since neutropenia can unexpectedly develop after treatment which may be compounded by the underlying disease and recent chemotherapy effects.

6594 Background: Acute myeloid leukemia (AML) patients who have prolonged neutropenia are at increased risk of morbidity and mortality due to invasive fungal infections. Voriconazole (VCZ), an effective antifungal prophylactic, is metabolized by the polymorphic CYP2C19 enzyme. Approximately 25% of individuals are genetically predicted to be CYP2C19 rapid metabolizers, thus at increased risk of breakthrough fungal infections due to low VCZ concentrations. We implemented a quality improvement pilot utilizing CYP2C19 genotype to optimize prophylactic VCZ dosing. Methods: AML patients with prolonged neutropenia are eligible for CYP2C19 genotyping (Luminex xTAG CYP2C19 Kit v3). Phenotypes are assigned per Clinical Pharmacogenetics Implementation Consortium guidelines. CYP2C19-guided recommendations for our quality improvement pilot are as follows: avoidance of VCZ in ultrarapid metabolizers, VCZ 300 mg twice daily (BID) for rapid metabolizers, and VCZ 200 mg BID for all other phenotypes. Therapeutic drug monitoring (TDM) is performed at the discretion of the medical team (goal trough concentration of 1-5.5 mcg/ml). Results: To date, 193 AML patients have undergone CYP2C19 genotyping; 3 (1.6%) ultrarapid, 50 (25.9%) rapid, 78 (40.4%) normal, 55 (28.5%) intermediate, and 7 (3.6%) poor metabolizers were observed. 154 patients (79.8%) received VCZ for prophylaxis, 11 (5.7%) for treatment, and 28 (14.5%) did not receive VCZ. Of the 154 patients receiving prophylactic VCZ, 137 (89%) were dosed per CYP2C19-guided recommendations. Pre-intervention (VCZ 200 mg BID) and post-intervention (VCZ 300 mg BID) VCZ trough concentrations were compared. Only 36.4% (4/11) of CYP2C19 rapid metabolizers receiving VCZ 200 mg BID achieved the goal trough concentration, whereas 75% (21/28) of rapid metabolizers receiving VCZ 300 mg BID achieved the goal trough concentration. CYP2C19-guided VCZ dosing resulted in trough concentrations in the target range for 70.1% (47/67) of all patients. Conclusions: Implementation of CYP2C19 genotyping to guide VCZ prophylactic dosing is feasible, with 70.1% of all patients having a VCZ goal trough concentration. Future analysis will determine if CYP2C19-guided VCZ dosing prevents breakthrough fungal infections.

Blinatumomab (BLN) is an anti-CD19 immunotherapy approved for relapsed/refractory (R/R) B-cell ALL with significantly increased survival rate. While BLN showed lower rates of infection, neutropenia and mucosal barrier injury (MBI) as compared with chemotherapy, its infection risks are not well described. BLN may also cause cytokine release syndrome and hypogammaglobulinemia. A retrospective review of the infectious risks and complications of BLN was performed for strategic antimicrobial prophylaxis. All patients who received BLN for ≥7 days at an academic cancer center from May 2015 to April 2017 were included. Patient characteristics pertinent to infectious risks and complications were examined. Twenty patients with refractory (25%), relapsed (70%), or remitted (5%) B-ALL who received a total of 35 cycles were included. A median of 2 previous chemotherapies were given (range 1–7). Ten of the 35 cycles were interrupted, none of which were due to infections except in a patient who had hypotension with mild ground glass pneumonia. Twenty-six infections (n) were observed with lower respiratory (9), gastrointestinal (6), and bacteremia (5) being most common. Four patients had nodular, probable mold pneumonia, 3 of which were newly developed on BLN. Compared with all patients, these patients had significantly lower absolute neutrophil count (ANC) on the first day of BLN (1897 vs. 208/µL, P = 0.045) and prolonged days of ANC <100/µL (3 vs. 8 days, P = 0.047). Among the four bacteremic patients, two patients received cytotoxic chemotherapy ≤ 3 days of the last BLN; 1 patient was discharged with no antibacterial since ANC recovered to >500/µL, but developed Pseudomonal bacteremia in a week with ANC ~ 100/µL. There was one 30-day mortality (noninfectious). Two patients were sent to hospice care <30 days of BLN with progressive disease, one of who also had infectious complications. Despite lack of MBI and mild neutropenia by BLN, host factors (e.g., duration and degree of neutropenia/lymphopenia, stage of ALL, chemotherapy pre- and post-BLN) play a key role in this population and should be considered in designing anti-mold coverage. In R/R disease, ANC should be monitored closely both inpatient and outpatient as neutropenia can worsen post BLN compounded by disease and other chemotherapy. All authors: No reported disclosures.

Macrolides and azalides have been widely utilized in clinical practice. With the increased use of these agents over the past two decades an accompanied increase in bacterial resistance as defined by laboratory based criteria has been observed. As a result, new derivatives have been introduced or are under development to overcome this emerging resistance. As the chemical structure of the macrolides progressed to the azalides and then ketolides, convenient once-daily oral dosing regimens and enhanced antibacterial activity over the earlier generation macrolides contributed to their widespread use for the treatment of community-acquired respiratory tract infections. As a result of the high penetration into respiratory tract tissues/fluids, the post antibiotic effect, uptake into white blood cells, and their immunomodulatory properties as well as their pharmacodynamic profile, the newer generation macrolides and azalides continue to be used in clinical practice with a high level of treatment success. Despite escalating macrolide resistance in target pathogens, the commercial withdrawal of telithromycin due to drug-related toxicities has tempered the development of new ketolides. The aims of this chapter are to provide principles to understand pharmacokinetic and pharmacodynamic properties of these agents and to provide insights supporting the application of this knowledge in clinical practice.

OBJECTIVES:While Amikacin Inhale (BAY41-6551), an integrated drug-device combination under development, achieves an estimated amikacin epithelial lining fluid (ELF) concentration of ∼ 5000 mg/L, its target site pharmacodynamics are unknown. We evaluated the pharmacodynamics of ELF exposure of inhaled amikacin ± meropenem.METHODS:ELF exposures of inhaled amikacin (400 mg every 12 h), intravenous meropenem (2 g every 8 h) and a combination of both were studied in an in vitro pharmacodynamic model. Seven Klebsiella pneumoniae and 10 Pseudomonas aeruginosa with amikacin/meropenem MICs of 1 to 32,768/≤ 0.125 to >128 mg/L were included. Efficacy was assessed over 24-72 h.RESULTS:The mean ± SD 0 h bacterial density was 6.5 ± 0.1 log10 cfu/mL. Controls grew to 8.0 ± 0.5 log10 cfu/mL by the end of the experiments. Simulation of inhaled amikacin monotherapy rapidly achieved and sustained bactericidal activity near the limit of detection over 24 h for all 13 isolates with amikacin MIC ≤ 256 mg/L except only ∼ 2 log10 cfu/mL reduction was observed in K. pneumoniae 375 (amikacin/meropenem MIC 64/32 mg/L) and P. aeruginosa 1544 (amikacin/meropenem MIC 64/128 mg/L). No activity was seen against the three isolates with amikacin MIC ≥ 2048 mg/L. Among the six isolates tested with meropenem monotherapy, five (meropenem MIC ≥ 16 mg/L) grew similarly to the controls while one (meropenem MIC 2 mg/L) achieved ∼ 2.5 log10 cfu/mL decrease. Among seven isolates tested in combination, four (amikacin/meropenem MIC ≤ 64/32 mg/L), including K. pneumoniae 375, maintained limit of detection until 72 h, whereas P. aeruginosa 1544 sustained a 1 log reduction. Combination therapy had no activity against the two isolates with amikacin MIC ≥ 2048 mg/L.CONCLUSIONS:Inhaled amikacin monotherapy showed bactericidal activity against most isolates tested with amikacin MICs ≤ 256 mg/L. Adjunct inhaled amikacin plus meropenem sustained this activity for 72 h for the tested isolates with amikacin/meropenem MIC ≤ 64/32 mg/L.

We assessed the efficacy and safety of cefepime monotherapy (1 g intravenously every 8 h) for febrile neutropenia in patients with lung cancer in a multi-institutional phase II study. Patients treated with chemotherapy with or without radiotherapy for lung cancer were eligible for this study. Other eligibility criteria included fever (temperature of ≥38.0 °C) and an absolute neutrophil count of <500/mm3 or <1000/mm3 with an expected decline to <500/mm3 within the next 48 h. Risk assessment was performed using the Multinational Association of Supportive Care in Cancer risk-index score. Cefepime 1 g was given intravenously every 8 h. The primary endpoint was the response rate at the end of cefepime therapy. Co-administration of granulocyte-colony-stimulating factor was permitted. Of 54 patients enrolled, 39 were classified in the low-risk group and 15 in the high-risk group. Overall response rate was 78% (95% CI: 64.4–88.0%). The response rates were 85% (95% CI: 69.5–94.1%) in the low-risk group and 60% (95% CI: 32.3–83.7%) in the high-risk group, respectively. One patient died from septic shock due to Enterobacter cloacae bacteremia. There was no significant adverse event. Cefepime 1 g intravenously every 8 h appears to be effective for febrile neutropenia in patients with lung cancer, especially in those with low-risk febrile neutropenia, and is well tolerated.UMIN Clinical Trials Registry, UMIN000006157.

ABSTRACT GSK2140944 is a novel bacterial type II topoisomerase inhibitor with in vitro activity against key causative respiratory pathogens, including methicillin-resistant Staphylococcus aureus (MRSA). We described the pharmacodynamics of GSK2140944 against MRSA in the neutropenic murine lung infection model. MICs of GSK2140944 were determined by broth microdilution. Plasma and epithelial lining fluid (ELF) pharmacokinetics were evaluated to allow determination of pulmonary distribution. Six MRSA isolates were tested. GSK2140944 doses of 1.56 to 400 mg/kg of body weight every 6 h (q6h) were utilized. Efficacy as the change in log 10 CFU at 24 h compared with 0 h controls and the area under the concentration-time curve for the free, unbound fraction of a drug ( f AUC)/MIC required for various efficacy endpoints were determined. GSK2140944 MICs were 0.125 to 0.5 mg/liter against the six MRSA isolates. ELF penetration ratios ranged from 1.1 to 1.4. Observed maximal decreases were 1.1 to 3.1 log 10 CFU in neutropenic mice. The mean f AUC/MIC ratios required for stasis and 1-log-unit decreases were 59.3 ± 34.6 and 148.4 ± 83.3, respectively. GSK2140944 displayed in vitro and in vivo activity against MRSA. The pharmacodynamic profile of GSK2140944, as determined, supports its further development as a potential treatment option for pulmonary infections, including those caused by MRSA.

Purpose: We assessed the effects of the urine matrix and its varying pH on the potency of the novel broad-spectrum fluoroquinolone delafloxacin and of ciprofloxacin against 16 urogenic Enterobacteriaceae in the urine of patients with suspected urinary tract infection.Materials and Methods: We determined minimum inhibitory concentrations in broth and urine using microdilution in 9 Escherichia coli and 7 Klebsiella pneumoniae specimens. The change in potency between broth and urine was calculated.Results: Against 16 highly ciprofloxacin resistant Enterobacteriaceae with a broth minimum inhibitory concentration of 32 mg/l or greater the minimum inhibitory concentration in delafloxacin in broth was 2 mg/l (1 and 0 isolates of E. coli and K. pneumoniae, respectively), 4 mg/l (3 and 0), 8 mg/l (3 and 1), 16 mg/l (2 and 4) and 32 mg/l (0 and 2). Across the 143 collected urines pH ranged from 4.7 to 9.0 with 71% at pH 6.5 or less. The delafloxacin minimum inhibitory concentration measured in 80% urine from 100 unique patient samples (pH 5.0 to 8.3) was 2 mg/l or less (18% and 0.8% for E. coli and K. pneumoniae, respectively), 4 mg/l (23% and 6%), 8 mg/l (21% and 18%), 16 mg/l (23% and 33%) and 32 mg/l or greater (15% and 42%). For E. coli and K. pneumoniae combined the median changes in the delafloxacin minimum inhibitory concentration were a 1 doubling dilution decrease at pH 6.0 or less, no change at pH 6.1 to 7.0 and a 1 doubling dilution increase at pH 7.1 or greater. Unlike delafloxacin, ciprofloxacin showed a 1 doubling dilution increase for E. coli and no change for K. pneumoniae at pH 7.0 or less with no change observed at pH 7.1 or greater.Conclusions: Most urines collected from patients with urinary tract infection had a pH of 6.5 or less. Delafloxacin broth minimum inhibitory concentrations were twofold to fivefold doubling dilutions lower than those of ciprofloxacin. In contrast to ciprofloxacin, the potency of delafloxacin was further enhanced in the acidic environment commonly observed in the setting of urinary tract infection.

While ceftriaxone 1 g q24h is commonly used for hospitalized patients with community-acquired pneumonia (CAP), the prescribing information recommends 2–4 g a day to treat methicillin-susceptible Staphylococcus aureus (MSSA). Similarly, recent pharmacodynamic analyses suggest shortcomings of 1 g q24h against the bulk of the MSSA. We evaluated the outcomes of empiric ceftriaxone 1 g q24h ± azithromycin in patients with MSSA pneumonia, as compared with Streptococcus pneumoniae. Adult patients admitted to Hartford Hospital from 1/2005 to 12/2014 with respiratory culture for MSSA or S. pneumoniae were considered for inclusion. Non-ICU, CAP patients were included. Early clinical failure (ECF) was defined as persistent signs/symptoms or change of antibiotic due to poor response at 72–96 h. A multivariate analysis was performed to evaluate predictors of ECF. Over the study period, 403 MSSA and 227 S. pneumoniae positive respiratory cultures were identified. The majority of patients were excluded due to the following: no signs/symptoms of pneumonia, hospital-acquired pneumonia, alternative antibiotics, and polymicrobial infection. Thirty-nine patients met inclusion/exclusion criteria. All but three patients in the S. pneumoniae group received ceftriaxone + azithromycin. ECF was greater in the MSSA group (53 vs. 4 %, P = 0.003), as was length of stay (7.5 ± 5.4 vs. 4.6 ± 3.3 days, P = 0.006). When controlling for disease severity and macrolide non-susceptibility in a multivariate analysis, MSSA was significantly correlated with ECF (OR 12.3, 95 % CI 0.8–188.8). Poor clinical outcomes were observed in patients empirically treated with ceftriaxone ± azithromycin for MSSA CAP. Despite the popularity of ceftriaxone 1 g q24h, these data suggest this dose or compound may be inadequate for CAP caused by MSSA.