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.

Pulmonary administration of polymyxins is increasingly used for the treatment of respiratory tract infections caused by multidrug-resistant Gram-negative bacteria, such as those in patients with cystic fibrosis. However, there is a lack of pharmacokinetics (PK), pharmacodynamics (PD), and toxicity data of aerosolized polymyxin B to inform rational dosage selection. The PK and PD of polymyxin B following pulmonary and intravenous dosing were examined in neutropenic infected mice, and the data were analyzed by a population PK model. Dose fractionation study was performed for total daily doses between 2.06 and 24.8 mg base/kg of weight against Pseudomonas aeruginosa ATCC 27853, PAO1, and FADDI-PA022 (MIC of 1 mg/liter for all three strains). Histopathological examination of the lung was undertaken at 24 h posttreatment in both healthy and neutropenic infected mice. A two-compartment PK model was required for both epithelial lining fluid (ELF) and plasma drug exposure. The model consisted of central and peripheral compartments and was described by bidirectional first-order distribution clearance. The ratio of the area under the curve to the MIC (AUC/MIC) was the most predictive PK/PD index to describe the antimicrobial efficacy of aerosolized polymyxin B in treating lung infections in mice (R 2 of 0.70 to 0.88 for ELF and 0.70 to 0.87 for plasma). The AUC/MIC targets associated with bacteriostasis against the three P. aeruginosa strains were 1,326 to 1,506 in ELF and 3.14 to 4.03 in plasma. Histopathological results showed that polymyxin B aerosols significantly reduced lung inflammation and preserved lung epithelial integrity. This study highlights the advantageous PK/PD characteristics of pulmonary delivery of polymyxin B over intravenous administration in achieving high drug exposure in ELF.

W e read with interest the report by Thamlikitkul et al. describing polymyxin B exposures in 19 adult patients with and without renal insufficiency (1). No significant difference was observed in the dose-normalized 24-h area under the concentration-time curve (AUC 24 ) at steady state between those with normal renal function, defined as an estimated creatinine clearance (CL CR ) of Ն80 ml/min (n ϭ 5; mean CL CR , 90.0 Ϯ 12.5 ml/min; mean AUC 24 , 28.6 Ϯ 7.0 mg · h/liter) and those with renal insufficiency (n ϭ 14; mean CL CR , 40.8 Ϯ 21.8 ml/min; mean AUC 24 , 29.7 Ϯ 11.2 mg · h/liter; P ϭ 0.80). A sensitivity analysis using lower CL CR threshold values of Ͻ60 and Ͻ40 ml/min yielded similar results.This study adds to mounting evidence that polymyxin B undergoes negligible renal excretion; thus, dose adjustment based solely on a patient's renal function may not be prudent (2, 3). Unfortunately, such observations conflict with current polymyxin B labeling, which instructs physicians to decrease doses in the setting of "renal impairment" (4). Administering less than the suggested 1.5 to 2.5 mg/kg of actual body weight daily may, in fact, be detrimental, increasing the risk of death as a consequence of insufficient drug exposure (5). However, the potential for nephrotoxicity and interpatient variability must also be considered when selecting polymyxin B dosing regimens (6). This raises two important questions: (i) what steps are necessary to provide clarity in polymyxin B dosing that will simultaneously achieve adequate pharmacodynamic (PD) response and minimize toxicodynamic (TD) events?; and (ii) how can we best apply information gained from the present (1) and previous (2, 3) studies to optimize polymyxin B dosing regimens?The first question may be answered by considering the overall paucity of polymyxin B clinical pharmacokinetic (PK) studies; with the inclusion of Thamlikitkul et al. 's cohort, the literature is composed of 65 patients' data (1-3, 7-10). While such reports conclude that polymyxin B doses should not be modified because of differences in renal function (1-3, 7-9), larger, prospective studies are necessary to confirm their findings. Such efforts are under way; a multicenter clinical study will enroll 250 critically ill patients treated with intravenous polymyxin B, assessing the drug's PK, PD, and TD characteristics, expanding the evidence base nearly 4-fold (NCT02682355). The solution to the second question lies in the ability to harness the predictive power of combining population PK models with adaptive feedback control to derive patient-specific PK information (11, 12). Leveraging population PK parameter estimates, their degree of interpatient variability, and measured drug concentrations, a Bayesian estimator indiCitation Onufrak NJ, Rao GG, Forrest A, Pogue JM, Scheetz MH, Nation RL, Li J, Kaye KS. 2017. Critical need for clarity in polymyxin B dosing. Antimicrob Agents Chemother 61:e00208-17.

Colistin has been administered via nebulization for the treatment of respiratory tract infections. Recently, dry powder inhalation (DPI) has attracted increasing attention. The current study aimed to investigate the pharmacokinetics (PK) of colistin in epithelial lining fluid (ELF) and plasma following DPI and intravenous (i.v.) administration in healthy Sprague-Dawley rats. Rats were given colistin as DPI intratracheally (0.66 and 1.32 mg base/kg of body weight) or i.v. injection (0.66 mg base/kg). Histopathological examination of lung tissue was performed at 24 h. Colistin concentrations in both ELF and plasma were quantified, and a population PK model was developed and compared to a previously published PK model of nebulized colistin in rats. A two-compartment structural model was developed to describe the PK of colistin in both ELF and plasma following pulmonary or i.v. administration. The model-estimated clearance from the central plasma compartment was 0.271 liter/h/kg (standard error [SE] = 2.51%). The transfer of colistin from the ELF compartment to the plasma compartment was best described by a first-order rate constant (clearance of colistin from the ELF compartment to the plasma compartment = 4.03 × 10 liter/h/kg, SE = 15%). DPI appeared to have a higher rate of absorption (time to the maximum concentration in plasma after administration of colistin by DPI, ≤10 min) than nebulization (time to the maximum concentration in plasma after administration of colistin by nebulization, 20 to 30 min), but the systemic bioavailabilities by the two routes of administration were similar (∼46.5%, SE = 8.43%). Histopathological examination revealed no significant differences in inflammation in lung tissues between the two treatments. Our findings suggest that colistin DPI is a promising alternative to nebulization considering the similar PK and safety profiles of the two forms of administration. The PK and histopathological information obtained is critical for the development of optimal aerosolized colistin regimens with activity against lung infections caused by Gram-negative bacteria.

Optimized dosage regimens of aerosolized colistin (as colistin methanesulfonate [CMS]) are urgently required to maximize bacterial killing against multidrug-resistant Gram-negative bacteria while minimizing toxicity. This study aimed to develop a mechanism-based pharmacokinetic (PK)/pharmacodynamic (PD) model (MBM) for aerosolized colistin based upon PK/PD data in neutropenic infected mice and to perform a deterministic simulation with the PK of aerosolized colistin (as CMS) in critically ill patients. time-kill experiments were carried out with three different strains of An MBM was developed in S-ADAPT and evaluated by assessing its ability to predict the PK/PD index associated with efficacy in mice. A deterministic simulation with human PK data was undertaken to predict the efficacy of current dosage regimens of aerosolized colistin in critically ill patients. In the final MBM, the total bacterial population for each isolate consisted of colistin-susceptible and -resistant subpopulations. The antimicrobial efficacy of aerosolized colistin was best described by a sigmoidal model whereby colistin enhanced the rate of bacterial death. Deterministic simulation with human PK data predicted that an inhalational dosage regimen of 60 mg colistin base activity (CBA) every 12 h is needed to achieve a ≥2-log bacterial reduction (as the number of CFU per lung) in critically ill patients at 24 h after commencement of inhaled therapy. In conclusion, the developed MBM is a useful tool for optimizing inhalational dosage regimens of colistin. Clinical studies are warranted to validate and refine our MBM for aerosolized colistin.