Linezolid is administered as a fixed dose to all patients despite evidence of increased exposure and myelosuppression in renal impairment. The objectives of these studies were to assess the risk of thrombocytopenia with standard-dose linezolid in renal impairment and to identify an alternate dosing strategy. In study 1, data from adult patients receiving linezolid for Ն10 days were retrospectively reviewed to determine the frequency of thrombocytopenia in patients with and without renal impairment. Time-to-event analyses were performed using Cox proportional-hazards models. In study 2, population pharmacokinetic modeling was employed to build covariatestructured models using an independent data set of linezolid concentrations obtained during routine therapeutic drug monitoring (TDM). Monte Carlo simulations were performed to identify linezolid dosing regimens that maximized attainment of therapeutic trough concentrations (2 to 8 mg/liter) across various renal-function groups. Toxicity analysis (study 1) included 341 patients, 133 (39.0%) with renal impairment. Thrombocytopenia occurred more frequently among patients with renal impairment (42.9% versus 16.8%; P Ͻ 0.001), and renal impairment was independently associated with this toxicity in multivariable analysis (adjusted hazard ratio [aHR], 2.37; 95% confidence interval [CI], 1.52 to 3.68). Pharmacokinetic analyses (study 2) included 1,309 linezolid concentrations from 603 adult patients. Age, body surface area, and estimated glomerular filtration rate (eGFR) were identified as covariates of linezolid clearance. Linezolid dose reductions improved the probability of achieving optimal exposures in simulated patients with eGFR values of Ͻ60 ml/min. Thrombocytopenia occurs more frequently in patients with renal impairment receiving standard linezolid doses. Linezolid dose reduction and trough-based TDM are predicted to mitigate this treatment-limiting toxicity.
Antibiotic renal dose adjustments are determined in subjects with stable chronic kidney disease and may not translate to patients in late phase trials and practice. Ceftolozane/tazobactam, ceftazidime/avibactam, and telavancin all carry precautionary statements for reduced clinical response in patients with baseline creatinine clearance 30 - 50 mL/min, potentially due to unnecessary dose reduction in the setting of acute kidney injury (AKI). In this review, we discuss the regulatory landscape for antibiotics eliminated by the kidney and highlight the importance of the first 48 hours of therapy. Using a clinical database, we identify AKI on admission in a substantial proportion of patients with pneumonia (27.1%), intra-abdominal (19.5%), urinary tract (20.0%), or skin and skin structure infections (9.7%) that resolved by 48 hours in 57.2% of cases. We suggest that deferred renal dose reduction of wide therapeutic index antibiotics could improve outcomes in patients with infectious diseases.
Renal function is the most commonly applied patient-specific quantitative variable used to determine drug doses. Measurement of renal function is not practical in most clinical settings; therefore, clinicians often rely on estimates when making dosing decisions. Similarly, renal function estimates are used to assign subjects in phase 1 pharmacokinetic studies, which inform dosing in late-phase clinical trials and ultimately the product label. The Cockcroft-Gault estimate of creatinine clearance has been the standard renal function metric; however, this paradigm is shifting toward the Modification of Diet in Renal Diseases (MDRD) estimate of the glomerular filtration rate (GFR). The proportion of approved new drug labels with dosing recommendations based on the MDRD equation was 16.7% in 2015, 70.0% in 2016, and 46.7% in 2017. Disharmonious recommendations from the United States Food and Drug Administration and the European Medicines Agency will continue to increase this heterogeneity in the assessment of renal function in drug development and negatively impact industry, health systems, and clinicians. In this review, we discuss the current regulatory guidance for the conduct of renal impairment pharmacokinetic studies and review the implications of this guidance across the medication use system with 3 recently approved antibiotics: ceftazidime/avibactam, delafloxacin, and meropenem/vaborbactam. Finally, we suggest measuring GFR in phase 1 studies and employing the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation to integrate data across clinical trials. This will help to harmonize CKD staging, population pharmacokinetic analyses, and dosing by estimated renal function.
Empirical vancomycin dosing informed by common clinical variables, including standardized creatinine, with subsequent individualization using AUC-targeted TDM can optimize therapy in obese and super obese adults.
Novel β‐lactamase inhibitors have extended the reach of new and existing β‐lactams against multidrug‐resistant bacteria expressing β‐lactamases. The efficacy of these combination therapeutics relies on a complex two‐component pharmacodynamic (PD) system where the β‐lactamase inhibitor inactivates the bacterial β‐lactamase enzyme and frees the companion β‐lactam to act against its penicillin‐binding protein target. Despite considerable investigation into the pharmacokinetics (PK) and pharmacodynamics of β‐lactams, the pharmacology of their companion β‐lactamase inhibitors has only recently been rigorously explored. This review describes the diversity of β‐lactamase enzymes, mechanisms of enzyme inhibition, and factors impacting the efficacy of clinically available β‐lactamase inhibitors. Relevant PK differences among available inhibitors and the PK/PD properties of these agents are described independently of their companion β‐lactams. In the modern era of antibiotic resistance, a comprehensive understanding of the pharmacology, PK, and PD of β‐lactamase inhibitors is paramount to maximizing the therapeutic efficacy of existing β‐lactam/β‐lactamase inhibitor combinations and protecting novel agents in the drug development pipeline.
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