SARS-CoV-2 utilizes the IMPα/β1 heterodimer to enter host cell nuclei after gaining cellular access through the ACE2 receptor. Ivermectin has shown antiviral activity by inhibiting the formation of the importin-α (IMPα) and IMPβ1 subunits as well as dissociating the IMPα/β1 heterodimer and has in vitro efficacy against SARS-CoV-2. Plasma and lung ivermectin concentrations vs. time profiles in cattle were used to determine the apparent plasma to lung tissue partition coefficient of ivermectin. This coefficient, together with a simulated geometric mean plasma profile of ivermectin from a published population pharmacokinetic model, was utilized to develop a minimal physiologically-based pharmacokinetic (mPBPK) model. The mPBPK model accurately described the simulated ivermectin plasma concentration profile in humans. The mPBPK model was also used to simulate human lung exposure to ivermectin after 12, 30, and 120 mg oral doses. The simulated ivermectin lung exposures reached a maximum concentration of 772 ng/mL, far less than the estimated 1750 ng/mL IC 50 reported for ivermectin against SARS-CoV-2 in vitro . Further studies of ivermectin either reformulated for inhaled delivery or in combination with other antivirals with differing mechanisms of action is needed to assess its therapeutic potential.

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Polymyxin B (PMB) has reemerged as a last-line therapy for infections caused by multidrug-resistant gram-negative pathogens, but dosing is challenging because of its narrow therapeutic window and pharmacokinetic (PK) variability.Population PK (POPPK) models based on suitably powered clinical studies with appropriate sampling strategies that take variability into consideration can inform PMB dosing to maximize efficacy and minimize toxicity and resistance.Here we reviewed published PMB POPPK models and evaluated them using an external validation data set (EVD) of patients who are critically ill and enrolled in an ongoing clinical study to assess their utility. Seven published POPPK models were employed using the reported model equations, parameter values, covariate relationships, interpatient variability, parameter covariance, and unexplained residual variability in NONMEM (Version 7.4.3). The predictive ability of the models was assessed using prediction-based and simulation-based diagnostics. Patient characteristics and treatment information were comparable across studies and with the EVD (n = 40), but the sampling strategy was a main source of PK variability across studies. All models visually and statistically underpredicted EVD plasma concentrations, but the two-compartment models more accurately described the external data set. As current POPPK models were inadequately predictive of the EVD, creation of a new POPPK model based on an appropriately powered clinical study with an informed PK sampling strategy would be expected to improve characterization of PMB PK and identify covariates to explain interpatient variability. Such a model would support modelinformed precision dosing frameworks, which are urgently needed to improve PMB treatment efficacy, limit resistance, and reduce toxicity in patients who are critically ill.

Antibiotic resistant bacterial respiratory infections are a significant global health burden, and new therapeutic strategies are needed to control the problem. For bacterial respiratory infections, this need is emphasized by the rise in antibiotic resistance and a lean drug development pipeline. Bacteriophage (phage) therapy is a promising alternative to antibiotics. Phage are viruses that infect and kill bacteria. Because phage and antibiotics differ in their bactericidal mechanisms, phage are a treatment option for antibiotic-resistant bacteria. Here, we review the history of phage therapy and highlight recent preclinical and clinical case reports of its use for treating antibiotic-resistant respiratory infections. The ability of phage to replicate while killing the bacteria is both a benefit for treatment and a challenge for pharmacokinetic (PK) and pharmacodynamic (PD) studies. In this review, we will discuss how the phage lifecycle and associated bidirectional interactions between phage and bacteria can impact treatment. We will also highlight PK/PD considerations for designing studies of phage therapy to optimize the efficacy and feasibility of the approach.

Mounting antimicrobial resistance to carbapenemase-producing Klebsiella pneumoniae (CPKP) highlights the need to optimize currently available treatment options. The objective of this study was to explore alternative dosing strategies that limit the emergence of resistance to preserve the utility of last-line antibiotics by: (i) evaluating the pharmacodynamic (PD) killing activity of simulated humanized exposures to monotherapy and two-drug and three-drug combinations against CPKP bacterial isolates with different resistance mechanisms; and (ii) optimizing polymyxin B (PMB) exposure simulated in the three-drug combination regimens to maximize the killing activity. Two CPKP clinical isolates (BAA2146 (NDM-1) and BRKP76 (KPC-2)) were evaluated over 168 hours using a hollow-fiber infection model simulating clinically relevant PMB, fosfomycin, and meropenem dosing regimens. PMB-based three-drug combinations were further optimized by varying the initial exposure (0-24 hours) or maintenance dose received over the duration of treatment. The area under the bacterial load-versus-time curve (AUCFU) was used to determine PD activity. Overall reductions in PMB exposure ranged from 2 to 84%. BAA2146 and BRKP76 had median (range) AUCFUs of 11.0 (10.6-11.6) log 10 CFU hour/mL and 7.08 (7.04-11.9) log 10 CFU hour/mL, respectively. The PMB "front loaded" 2.5 mg/ kg/day + 0.5 mg/kg maintenance dose in combination with meropenem and fosfomycin was a promising regimen against BRKP76, with an overall reduction in PMB exposure of 56% while still eradicating the bacteria. Tailored triplecombination therapy allows for the optimization of dose and treatment duration of last-line agents like PMB to achieve adequate drug exposure and appropriate PD activity while minimizing the emergence of resistance.