Purpose of review Carbapenem-resistant organisms (CROs), including Pseudomonas aeruginosa, Acinetobacter baumannii and Enterobacterales, are a threat worldwide. This review will cover mechanisms of resistance within CROs and challenges with identification and treatment of these organisms while pointing out unresolved issues and ongoing challenges. Recent findings The treatment of CROs has expanded through newer therapeutic options. Guided utilization through genotypic and phenotypic testing is necessary in order for these drugs to target the appropriate mechanisms of resistance and select optimal antibiotic therapy. Summary Identification methods and treatment options need to be precisely understood in order to limit the spread and maximize outcomes of CRO infections.

Epstein-Barr virus (EBV)-associated posttransplant lymphoproliferative disorder(EBV-PTLD) is a serious complication in lung transplant recipients (LTRs) associated with significant mortality. We performed a single-center retrospective study to evaluate the risks for PTLD in LTRs over a 7-year period. Of 611 evaluable LTRs, we identified 28 cases of PTLD, with an incidence of 4.6%. Kaplan-Meier analysis showed a decreased freedom from PTLD in idiopathic pulmonary fibrosis (IPF)-LTRs (P < .02). Using a multivariable Cox proportional hazards model, we found IPF (hazard ratio [HR] 3.51, 95% confidence interval [CI] 1.33-8.21, P = .01) and alemtuzumab induction therapy (HR 2.73, 95% CI 1.10-6.74, P = .03) as risk factors for PTLD, compared to EBV mismatch (HR: 34.43, 95% CI 15.57-76.09, P < .0001). Early PTLD (first year) was associated with alemtuzumab use (P = .04), whereas IPF was a predictor for late PTLD (after first year) (P = .002), after controlling for age and sex. Kaplan-Meier analysis revealed a shorter time to death from PTLD in IPF LTRs compared to other patients (P = .04). The use of alemtuzumab in EBV mismatch was found to particularly increase PTLD risk. Together, our findings identify IPF LTRs as a susceptible population for PTLD. Further studies are required to understand the mechanisms driving PTLD in IPF LTRs and develop strategies to mitigate risk. K E Y W O R D S clinical research/practice, hematology/oncology, immunosuppression/immune modulation, immunosuppressive regimens -induction, infection and infectious agents -viral: Epstein-Barr virus (EBV), lung disease, lung transplantation/pulmonology, posttransplant lymphoproliferative disorder (PTLD)

Background Two of the three recently approved β-lactam agent (BL)/β-lactamase inhibitor (BLI) combinations have higher CLSI susceptibility breakpoints (ceftazidime/avibactam 8 mg/L; meropenem/vaborbactam 4 mg/L) compared with the BL alone (ceftazidime 4 mg/L; meropenem 1 mg/L). This can lead to a therapeutic grey area on susceptibility reports depending on resistance mechanism. For instance, a meropenem-resistant OXA-48 isolate (MIC 4 mg/L) may appear as meropenem/vaborbactam-susceptible (MIC 4 mg/L) despite vaborbactam’s lack of OXA-48 inhibitory activity. Methods OXA-48-positive (n = 51) and OXA-48-negative (KPC, n = 5; Klebsiella pneumoniae wild-type, n = 1) Enterobacterales were utilized. Susceptibility tests (broth microdilution) were conducted with ceftazidime/avibactam, imipenem/relebactam and meropenem/vaborbactam, as well as their respective BL partner. Antimicrobial activity of all six agents was evaluated in the murine neutropenic thigh model using clinically relevant exposures. Efficacy was assessed as the change in bacterial growth at 24 h, compared with 0 h controls. Results On average, the three BL/BLI agents resulted in robust bacteria killing among OXA-48-negative isolates. Among OXA-48-positive isolates, poor in vivo activity with imipenem/relebactam was concordant with its resistant phenotypic profile. Variable meropenem/vaborbactam activity was observed among isolates with a ‘susceptible’ MIC of 4 mg/L. Only 30% (7/23) of isolates at meropenem/vaborbactam MICs of 2 and 4 mg/L met the ≥1-log bacterial reduction threshold predictive of clinical efficacy in serious infections. In contrast, ceftazidime/avibactam resulted in marked bacterial density reduction across the range of MICs, and 96% (49/51) of isolates exceeded the ≥1-log bacterial reduction threshold. Conclusions Data demonstrate that current imipenem/relebactam and ceftazidime/avibactam CLSI breakpoints are appropriate. Data also suggest that higher meropenem/vaborbactam breakpoints relative to meropenem can translate to potentially poor clinical outcomes in patients infected with OXA-48-harbouring isolates.

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Objectives Previous investigations into metallo-β-lactamase (MBL)-harbouring Enterobacterales suggest that susceptibility testing in zinc-limited media may be more appropriate in predicting β-lactam in vivo activity. There are limited data with MBL-harbouring Pseudomonas aeruginosa. Methods Forty-three MBL-harbouring P. aeruginosa isolates (IMP, n = 11; VIM, n = 12; NDM, n = 10; SPM, n = 10) and two P. aeruginosa control isolates (KPC, n = 1; WT, n = 1) were evaluated. Meropenem activity was evaluated in the murine neutropenic thigh model using humanized exposures. Susceptibility testing was conducted in conventional CAMHB, EDTA-supplemented CAMHB (3–300 mg/L EDTA) and Chelex-treated CAMHB (0–1.0 mg/L re-supplemented zinc), resulting in a range of meropenem MIC values for each isolate. A sigmoidal Emax model was fitted to fT&gt;MIC versus change in log10 cfu/thigh to estimate the goodness of fit (R2). Results Increasing EDTA concentrations or limiting the amount of zinc in broth resulted in several-fold reductions in MIC among the majority of the MBL-harbouring P. aeruginosa while the MICs for the KPC and WT isolates were unchanged. Bacterial killing in vivo was variable, with the range of killing spanning −3.29 to +4.81 log10 change in cfu/thigh. Addition of 30 mg/L EDTA and Chelex-treated CAMHB (with no zinc supplementation) provided broth conditions for susceptibility testing that best predicted in vivo efficacy (R2 &gt; 0.7). Conclusions Among MBL-harbouring P. aeruginosa, meropenem in vivo efficacy is best represented by the pharmacodynamic profile generated using MICs determined in EDTA-supplemented or zinc-limited broth. In addition to previous data with Enterobacterales, antibiotic susceptibility testing in media that approximates physiological conditions makes it possible to uncover potential and existing therapeutic agents.

Background ECMO is a life-saving tool utilized in critically ill patients that require respiratory and/or cardiac support. ECMO may also affect the pharmacokinetics (PK) of certain medications, including some antibiotics. Cefepime is a widely used antibiotic in this population due to its broad spectrum activity but limited data are available to guide dosing in patients requiring ECMO. Methods This was a prospective, single-center study of 6 critically ill adult patients requiring ECMO and receiving cefepime 2g q8h as a 3h infusion. After obtaining informed consent, 4-6 blood samples within the dosing interval were collected to determine cefepime concentrations. Population PK was conducted in Pmetrics using R. Final MAP Bayesian parameter estimates were used to simulate free time above MIC (%ƒT &gt;MIC) for various cefepime dosing regimens. The target pharmacodynamic exposure was 70% fT &gt;MIC. Results Patients were between 31-62 years old; 4/6 (66.7%) were on veno-venous (VV) ECMO and 2 veno-arterial (VA) ECMO. Two patients required continuous venovenous hemodiafiltration (CVVHDF) while the other 4 had a CrCL between 92-199 ml/min. A two compartment model fitted the data better than a one compartment model. Median (range) final population PK parameters were: clearance (CL), 9.8 L/h (7.6-33.1); volume of central compartment (VC ), 6.9 L (4.7-49.8); and intercompartment transfer constants (k12), 2.04 h-1 (1.48-2.29); and k21, 1.49 h-1 (0.75-1.71). The 2g q8h (3h infusion) regimen resulted in target exposure in all patients up to an MIC of 8 mg/L (the susceptibility breakpoint for Pseudomonas), with 5/6 patients achieving this at 16 mg/L. A standard 2g q12h (0.5h infusion) regimen would have resulted in 5/6 patients achieving 70% ƒT &gt;MIC at 8 mg/L and 1/6 at 16 mg/L. Conclusion These are the first data describing cefepime PK and exposure attainment in critically ill patients receiving ECMO. Cefepime 2g q8h (3h infusion) achieved target pharmacodynamic exposure up to the susceptibility breakpoint of 8 mg/L in all 6 patients, including 2 with concomitant CVVHDF. Additional studies are warranted to define cefepime PK in patients on ECMO across a robust range of CrCL to guide dosing. Disclosures David P. Nicolau, PharmD, Abbvie, Cepheid, Merck, Paratek, Pfizer, Wockhardt, Shionogi, Tetraphase (Other Financial or Material Support, I have been a consultant, speakers bureau member, or have received research funding from the above listed companies.) Joseph L. Kuti, PharmD, Allergan (Speaker’s Bureau)BioMérieux (Consultant, Research Grant or Support, Speaker’s Bureau)Contrafect (Scientific Research Study Investigator)GSK (Consultant)Merck (Research Grant or Support)Paratek (Speaker’s Bureau)Roche Diagnostics (Research Grant or Support)Shionogi (Research Grant or Support)Summit (Scientific Research Study Investigator)

Background Two out of the three recently approved β-lactam (BL)/β-lactamase inhibitors (BLIs) have higher CLSI susceptibility breakpoints (ceftazidime/avibactam 8 mg/L; meropenem/vaborbactam 4 mg/L) compared with the BL alone (ceftazidime 4 mg/L; meropenem 1 mg/L). This can lead to a therapeutic grey area on susceptibility reports depending on resistance mechanism. For instance, a meropenem-resistant OXA-48 isolate (MIC 4 mg/L) may appear as meropenem/vaborbactam-susceptible (MIC 4 mg/L) despite vaborbactam’s lack of OXA-48 inhibitory activity. Methods OXA-48-positive (n = 51) and OXA-48-negative (KPC, n = 5; Klebsiella pneumoniae WT, n = 1) Enterobacterales were utilized. Susceptibility tests (broth microdilution) were conducted with ceftazidime/avibactam, imipenem/relebactam and meropenem/vaborbactam, as well as their respective BL partner. Antimicrobial activity of all six agents was evaluated in the murine neutropenic thigh model using clinically relevant exposures. Efficacy was assessed as the change in bacterial growth at 24 h, compared with 0 h controls. Results On average, the three BL/BLI agents resulted in robust bacteria killing among OXA-48-negative isolates. Among OXA-48-positive isolates, poor in vivo activity with imipenem/relebactam was concordant with its resistant phenotypic profile. Variable meropenem/vaborbactam activity was observed among isolates with a ‘susceptible’ MIC of 4 mg/L. Only 30% (7/23) of isolates at meropenem/vaborbactam MICs of 2 and 4 mg/L met the ≥1 log bacterial reduction threshold predictive of clinical efficacy in serious infections. In contrast, ceftazidime/avibactam resulted in marked bacterial density reduction across the range of MICs and 73% (37/51) of isolates exceeded the ≥1 log bacterial reduction threshold. Conclusions Data demonstrate that current imipenem/relebactam and ceftazidime/avibactam CLSI breakpoints are appropriate. Data also suggest that higher meropenem/vaborbactam breakpoints relative to meropenem can translate to potentially poor clinical outcomes in patients infected with OXA-48-harbouring isolates.

BackgroundAppropriate empiric antibiotic therapy is associated with decreased mortality and recurrence in patients with Enterobacteriaceae bacteremia (EB). Increasing bacterial resistance adds an additional layer to this complex clinical scenario. Swift utilization of appropriate antibiotics is crucial for improved patient outcomes. However, prolonged and excessively broad antibiotic coverage is not without its own complications. Our study aimed to review the appropriateness of empiric antibiotics for EB.MethodsA retrospective chart review of all patients >18 years of age who were admitted to a single academic community hospital during 2018 EB anytime throughout their hospitalization. The primary endpoint was the appropriateness of empiric antibiotic therapy, defined as receiving active therapy prior to the return of antimicrobial sensitivities that were susceptible to the empiric agents used. Appropriateness was further adjusted for standard of care (SOC) practices. Specifically, despite in vitro susceptibility of piperacillin/tazobactam and cefepime, carbapenem therapy is preferred for ESBL infections.ResultsOur study identified 178 patients with EB. Most common organisms included E.coli (64.6%), K. pneumoniae (11.8%) and P. mirabilis (7.3%). Resistance patterns included 1 CRE (0.57%) and 17 ESBL (9.7%) isolates. Most common sources of infection included urinary (63.5%) and intraabdominal (13.5%). Based on the sensitivity reports of tested isolates, 83.7% of patients received appropriate empiric antibiotics. After adjustment for SOC, 11.8% of ESBL patients (2/17) and 0% of CRE (0/1) patients received appropriate therapy. Comparatively 89.0% of patients without ESBL or CRE (137/154) received appropriate care (P < 0.0001).ConclusionThe results of this study demonstrate that across our patient population, over 80% of patients received appropriate empiric antibiotics for EB; however, this percentage was dramatically lower for patients with ESBL or CRE infections. This highlights room for improved rapid diagnosis and identification of risk factors predisposing to resistant organisms thereby decreasing the time to appropriate antibiotic therapy. Disclosures All authors: No reported disclosures.