Pharmacokinetic and Pharmacodynamic Principles of Anti-infective Dosing

Abstract

Purpose An understanding of the pharmacokinetic (PK) and pharmacodynamic (PD) principles that determine response to antimicrobial therapy can provide the clinician with better-informed dosing regimens. Factors influential on antibiotic disposition and clinical outcome are presented, with a focus on the primary site of infection. Techniques to better understand antibiotic PK and optimize PD are acknowledged. Methods PubMed (inception – April 2016) was reviewed for relevant publications assessing antimicrobial exposures within different anatomical locations and clinical outcomes for various infection sites. Findings A limited literature base indicates variable penetration of antibiotics to different target sites of infection, with drug solubility and extent of protein binding providing significant PK influences in addition to the major clearing pathway of the agent. PD indices derived from in vitro and animal models determine the optimal magnitude and frequency of dosing regimens for patients. PK/PD modeling and simulation has been shown an efficient means of assessing these PD endpoints against a variety of PK determinants, clarifying the unique effects of infection site and patient characteristics to inform the adequacy of a given antibiotic regimen. Implications Appreciation of the PK properties of an antibiotic and its PD measure of efficacy can maximize the utility of these life-saving drugs. Unfortunately, clinical data remains limited for a number of infection site-antibiotic exposure relationships. Modeling and simulation can bridge preclinical and patient data for the prescription of optimal antibiotic dosing regimens, consistent with the tenets of personalized medicine.

Bolus Administration of Polyamines Boosts Effects on Hepatic Ischemia-Reperfusion Injury and Regeneration in Rats

“…This finding is supported by other publications reporting that bolus administration of polyamines significantly attenuates injury or promotes regeneration [6, 7, 9, 10]. Additionally, it is also supported by pharmacokinetics/pharmacodynamics theory in pharmacy, which describes the time course of effect intensity in response to administration of an antibiotics dose [17]. …”

Selecting the dosage of ceftazidime–avibactam in the perfect storm of nosocomial pneumonia

“…Establishing PK/PD targets for NP and VAP Population PK modeling and PTA analyses using PK/PD targets derived from preclinical data are commonly used to guide and support the selection of appropriate antibiotic dosage regimens for clinical use [40][41][42][43]. Achievement of 50% free drug time above the MIC (fT>MIC) is an established PD target for ceftazidime that is associated with up to 2 log 10 killing of Enterobacteriaceae and P. aeruginosa in neutropenic mouse infection models [44][45][46], and with microbiological eradication in patients with NP caused by Gram-negative pathogens [47,48].…”

Optimizing Antibiotic Drug Therapy in Pediatrics: Current State and Future Needs

“…For pneumonia caused by extracellular pathogens, epithelial lining fluid (ELF) has been used as the target site to determine adequacy of drug exposure. Currently, the literature on ELF‐to‐plasma ratios is limited to a small number of antibiotics, all of which were evaluated in adults, and comprises beta‐lactams (ranging from 0.21 to 1.04, depending on the specific beta‐lactam), vancomycin (0.18 to 0.50), aminoglycosides (highly variable hysteresis depending on sampling time and arising from the hydrophilic property of these antibiotics), and fluoroquinolones (>1.0, which represents extensive lung penetration) . The presence of hysteresis on a concentration‐effect plot implies a delay in time between measured concentration and response, as well as an associated lower peak concentration.…”

“…Currently, the literature on ELF-to-plasma ratios is limited to a small number of antibiotics, all of which were evaluated in adults, and comprises beta-lactams (ranging from 0.21 to 1.04, depending on the specific beta-lactam), vancomycin (0.18 to 0.50), aminoglycosides (highly variable hysteresis depending on sampling time and arising from the hydrophilic property of these antibiotics), and fluoroquinolones (>1.0, which represents extensive lung penetration). 30 The presence of hysteresis on a concentration-effect plot implies a delay in time between measured concentration and response, as well as an associated lower peak concentration. Notably, these studies of ELF do not account for redistribution of drugs from the ELF back to plasma because only specific time points after dose administration (rather than over the entire dosing interval) were evaluated.…”