Background To date, no real-world data are available to describe cefiderocol use in carbapenem-resistant Acinetobacter baumannii (CRAB) meningitis. Furthermore, cefiderocol pharmacokinetic (PK) data to support CNS penetration in human subjects are limited. These gaps pose a significant concern for clinicians who are faced with treating such infections when considering cefiderocol use. Objectives To describe cefiderocol CSF and plasma PK and pharmacodynamic (PD) data from two different dosing regimens [2 g IV q6h (regimen 1) and 2 g IV q8h (regimen 2)] during treatment of CRAB meningitis. Patients and methods A 61-year-old woman with CRAB meningitis was treated with cefiderocol and intraventricular gentamicin. Steady-state plasma and CSF cefiderocol concentrations were evaluated on Day 19 (regimen 1) and Day 24 (regimen 2) during the cefiderocol treatment course. Results CSF AUC was 146.49 and 118.28 mg·h/L, as determined by the linear-log trapezoidal method for regimens 1 and 2, respectively. Penetration into CSF estimated as the AUCCSF/AUCfree plasma ratio was 68% and 60% for regimens 1 and 2, respectively. Estimated free plasma and CSF concentrations exceeded the MIC of the isolate for 100% of the dosing interval. Microbiological and clinical cure were achieved, and no cefiderocol-associated adverse effects were observed. Conclusions Cefiderocol, when given as 2 g q8h and 2 g q6h, attained CSF concentrations that exceeded the organism-specific MIC and the CLSI susceptible breakpoint (≤4 mg/L) for 100% of the dosing interval.

Background Sulbactam (SUL), available in the USA as ampicillin-sulbactam, is a first line treatment for Acinetobacter baumannii infections. SUL is bactericidal against A. baumannii through affinity to penicillin-binding proteins with no synergy upon ampicillin addition. Despite its wide use, SUL dosing has not been standardized for management of A. baumannii infections. Herein, we examined SUL pharmacokinetic/pharmacodynamic (PK/PD) targets against A. baumannii in a neutropenic murine pneumonia model followed by estimation of the probability of target attainment (PTA) across a range of clinical SUL doses. Methods Eight clinical A. baumannii isolates (SUL MICs 1–16 mg/L) were tested. Mice were inoculated intranasally with 107 colony forming units (CFU)/mL bacterial suspensions. Two hours post inoculation, escalating SUL doses (1–200 mg/kg) were administered q8h for 24 h as ampicillin-sulbactam, while control mice received saline. Efficacy was measured as the change in log10 CFU/ lungs at 24 h compared with 0 h controls. PK and ex vivo protein binding of SUL were assessed in infected mice to determine the free systemic exposures of the regimens utilized. The percentages of dosing interval in which the free plasma concentration exceeded the SUL MIC (%fT > MIC) required to achieve 1- and 2-log kill against each isolate were estimated using Hill-equation. Monte Carlo simulations were performed to determine PTA for these endpoints with various clinically-utilized SUL dosing regimens. Mean and standard deviation values for SUL PK parameters were derived from patients with nosocomial pneumonia due to A. baumannii. Results Median (Interquartile range, IQR) %fT > MIC needed for 1-log and 2-log kill at 24 h were 27.36 (19.94 – 35.11) and 48.36 (38.18 – 58.01), respectively. The corresponding PTA following the maximum FDA-approved SUL dose for pneumonia (1g q6h, 0.5 h infusion) and three off-label doses are reported in the table. Conclusion Currently approved dose of SUL for pneumonia (1g q6h, 0.5 h infusion) provides effective exposure against A. baumannii at the current FDA/CLSI susceptibility breakpoint (SUL MIC ≤ 4 mg/L). Higher and/or more frequent SUL dosing provides additional coverage with 3 g q8h extended infusion further enhancing the PK/PD exposure against isolates with SUL MICs up to 16 mg/L. Disclosures Yasmeen Abouelhassan, PhD, Pfizer: spouse salary Joseph L. Kuti, PharmD, Abbvie: Honoraria|bioMeriuex: Advisor/Consultant|bioMeriuex: Grant/Research Support|Contrafect: Grant/Research Support|Entasis: Grant/Research Support|Merck and Co: Grant/Research Support|Roche Diagnostics: Grant/Research Support|Shionogi: Advisor/Consultant|Shionogi: Grant/Research Support|Shionogi: Honoraria|Summit: Grant/Research Support David P. Nicolau, PharmD, Shionogi: Grant/Research Support Kamilia Abdelraouf, PhD, Evopoint Biosciences Co., Ltd: Grant/Research Support|Venatorx Pharmaceuticals, Inc.: Grant/Research Support.

Antimicrobial treatments for extensively drug-resistant Acinetobacter baumannii (XDR-AB) infections have proven lackluster while dosing challenges in patients receiving continuous renal replacement therapy continue. We describe a patient receiving cefiderocol, ampicillin/sulbactam, and tigecycline for XDR-AB while undergoing CVVHDF. The clinical course, cefiderocol and sulbactam pharmacokinetics, as well as synergy assessments are described.

Hospital-acquired pneumonia (HAP) and ventilator-associated pneumonia (VAP) are correlated with high mortality rates worldwide. Thus, the administration of antibiotic therapy with appropriate dosing regimen is critical. An efficient antibiotic is needed to maintain an adequate concentration at the infection site, for a sufficient period of time, to achieve the best therapeutic outcome. It can, however, be challenging for antibiotics to penetrate the pulmonary system due to the complexity of its structure. Crossing the blood alveolar barrier is a difficult process determined by multiple factors that are either drug related or infection related. Thus, the understanding of pharmacokinetics/pharmacodynamics (PK/PD) of antibiotics identifies the optimum dosing regimens to achieve drug penetration into the epithelial lining fluid at adequate therapeutic concentrations. Critically ill patients in the ICU can express augmented renal clearance (ARC), characterized by enhanced renal function, or may have renal dysfunction necessitating supportive care such as continuous renal replacement therapy (CRRT). Both ARC and CRRT can alter drug elimination, thus affecting drug concentrations. PK of critically ill patients is less clear due to the multiple variabilities associated with their condition. Therefore, conventional dosing regimens often lead to therapeutic failure. Another major hurdle faced in optimizing treatment for HAP/VAP is the reduction of the in vitro potency. Therapeutic drug monitoring (TDM), if available, may allow health care providers to personalize treatment to maximize efficacy of the drug exposures while minimizing toxicity. TDM can be of significant importance in populations whom PK are less defined and for resistant infections to achieve the best therapeutic outcome.

Background Administration of the oral carbapenem, tebipenem along with its broad spectrum of activity against anaerobic, Gram-positive and Gram-negative pathogens including extended-spectrum β-lactamase-producing Enterobacterales, offers clinicians a potential new option and route to treat a range of infections. Lower extremity infections in diabetic patients are associated with high rates of hospitalization and amputation. Given the microvascular dysfunction and poor peripheral circulation in this population, the aim of this study was to assess tebipenem soft tissue pharmacokinetics (PK) and interstitial fluid distribution among diabetic patients with lower extremity infections using in vivo microdialysis. Methods This was a single-center, open-label, observational PK study in diabetic patients with foot infections who were enrolled and received tebipenem (600 mg) orally q8 hrs for a total of 3 doses. A microdialysis catheter was inserted within 4-8 cm of the wound margin to allow for dialysate sampling. Ten concurrent plasma and dialysate samples over an 8 hr period starting immediately prior to the last dose of tebipenem were obtained. Protein binding was determined by ultracentrifugation at 1 hr post-third dose. Plasma and dialysate samples were assayed via a validated LC/MS/MS assay. Non-compartmental analyses for free plasma and soft-tissue concentration were used to obtain PK parameters. Results Four male diabetic patients with an age of 70 ± 7 years and a hemoglobin A1C of 10 ± 2% were consented. All patients had an active complicated skin and soft tissue infection as defined by PEDIS Grade 2 or 3. Mean ± standard deviation (SD) plasma protein binding was 50% ± 1%. Mean ± SD tebipenem PK parameters in plasma were: maximum free concentration (fCmax), 2.34 ± 0.94 mg/L; time to Cmax (Tmax), 2.99 ± 1.40 hr; half-life (t1/2), 2.23 ± 1.65 hr and free area under the concentration-time curve (fAUCp(0-8)): 8.37 ± 1.63 mg.h/L. Mean ± SD parameters in tissue were: Cmax, 2.50 ± 1.04 mg/L; Tmax, 2.99 ± 1.40 h; t1/2 1.99 ± 1.42 hr; and AUCt(0-8), 8.01 ± 0.76 mg.h/L. Conclusion This study demonstrates that tebipenem has excellent distribution into interstitial fluid and lower extremity tissue of diabetic patients with ongoing foot infections. Disclosures Yasmeen Abouelhassan, PhD, Pfizer: spouse salary David P. Nicolau, PharmD, Shionogi: Grant/Research Support.