Theoretical considerations and empirical predictions of the pharmaco- and population dynamics of heteroresistance.

Antibiotics are considered one of the most important contributions to clinical medicine in the last century. Due to the use and overuse of these drugs, there have been increasing frequencies of infections with resistant pathogens. One form of resistance, heteroresistance, is particularly problematic; pathogens appear sensitive to a drug by common susceptibility tests. However, upon exposure to the antibiotic, resistance rapidly ascends, and treatment fails. To quantitatively explore the processes contributing to the emergence and ascent of resistance during treatment and the waning of resistance following cessation of treatment, we develop two distinct mathematical and computer-simulation models of heteroresistance. In our analysis of the properties of these models, we consider the factors that determine the response to antibiotic-mediated selection. In one model, heteroresistance is progressive, with each resistant state sequentially generating a higher resistance level. In the other model, heteroresistance is non-progressive, with a susceptible population directly generating populations with different resistance levels. The conditions where resistance will ascend in the progressive model are narrower than those of the non-progressive model. The rates of reversion from the resistant to the sensitive states are critically dependent on the transition rates and the fitness cost of resistance. Our results demonstrate that the standard test used to identify heteroresistance is insufficient. The predictions of our models are consistent with empirical results. Our results demand a reevaluation of the definition and criteria employed to identify heteroresistance. We recommend that the definition of heteroresistance should include a consideration of the rate of return to susceptibility.

International Union of Basic and Clinical Pharmacology. CXV: The Class F of G Protein-Coupled Receptors.

The class F of G protein-coupled receptors (GPCRs) consists of ten Frizzleds (FZD1-10) and Smoothened (SMO). FZDs bind and are activated by secreted lipoglycoproteins of the Wingless/Int-1 (WNT) family and SMO is indirectly activated by the Hedgehog (Hh) family of morphogens acting on the transmembrane protein Patched (PTCH). The advance of our understanding of FZDs and SMO as dynamic transmembrane receptors and molecular machines, which emerged during the past 14 years since the first class F GPCR IUPHAR nomenclature report, justifies an update. This article focuses on the advances in molecular pharmacology and structural biology providing new mechanistic insight into ligand recognition, receptor activation mechanisms, signal initiation and signal specification. Furthermore, class F GPCRs continue to develop as drug targets, and novel technologies and tools such as genetically encoded biosensors and CRISP/Cas9 edited cell systems have contributed to refined functional analysis of these receptors. Also, advances in crystal structure analysis and cryogenic electron microscopy contribute to a rapid development of our knowledge about structure-function relationships providing a great starting point for drug development. Despite the progress questions and challenges remain to fully understand the complexity of the WNT/FZD and Hh/SMO signaling systems. Significance Statement The recent years of research have brought about substantial functional and structural insight into mechanisms of activation of Frizzleds and Smoothened. While the advance furthers our mechanistic understanding of ligand recognition, receptor activation, signal specification and initiation, broader opportunities emerge that allow targeting class F GPCRs for therapy and regenerative medicine employing both biologics and small molecule compounds.

Pharmacokinetics and pharmacodynamics of bacteriophage therapy: a review with a focus on multidrug-resistant Gram-negative bacterial infections.

SUMMARYDespite the early recognition of their therapeutic potential and the current escalation of multidrug-resistant (MDR) pathogens, the adoption of bacteriophages into mainstream clinical practice is hindered by unfamiliarity with their basic pharmacokinetic (PK) and pharmacodynamic (PD) properties, among others. Given the self-replicative nature of bacteriophages in the presence of host bacteria, the adsorption rate, and the clearance by the host's immunity, their PK/PD characteristics cannot be estimated by conventional approaches, and thus, the introduction of new considerations is required. Furthermore, the multitude of different bacteriophage types, preparations, and treatment schedules impedes drawing general conclusions on their in vivo PK/PD features. Additionally, the drawback of acquired bacteriophage resistance of MDR pathogens with clinical and environmental implications should be taken into consideration. Here, we provide an overview of the current state of the field of PK and PD of bacteriophage therapy with a focus on its application against MDR Gram-negative infections, highlighting the potential knowledge gaps and the challenges in translation from the bench to the bedside. After reviewing the in vitro PKs and PDs of bacteriophages against the four major MDR Gram-negative pathogens, Klebsiella pneumoniae, Acinetobacter baumannii complex, Pseudomonas aeruginosa, and Escherichia coli, specific data on in vivo PKs (tissue distribution, route of administration, and basic PK parameters in animals and humans) and PDs (survival and reduction of bacterial burden in relation to the route of administration, timing of therapy, dosing regimens, and resistance) are summarized. Currently available data merit close scrutiny, and optimization of bacteriophage therapy in the context of a better understanding of the underlying PK/PD principles is urgent to improve its therapeutic effect and to minimize the occurrence of bacteriophage resistance.

Challenges for global antibiotic regimen planning and establishing antimicrobial resistance targets: implications for the WHO Essential Medicines List and AWaRe antibiotic book dosing.

SUMMARYThe World Health Organisation's 2022 AWaRe Book provides guidance for the use of 39 antibiotics to treat 35 infections in primary healthcare and hospital facilities. We review the evidence underpinning suggested dosing regimens. Few (n = 18) population pharmacokinetic studies exist for key oral AWaRe antibiotics, largely conducted in homogenous and unrepresentative populations hindering robust estimates of drug exposures. Databases of minimum inhibitory concentration distributions are limited, especially for community pathogen-antibiotic combinations. Minimum inhibitory concentration data sources are not routinely reported and lack regional diversity and community representation. Of studies defining a pharmacodynamic target for ß-lactams (n = 80), 42 (52.5%) differed from traditionally accepted 30%-50% time above minimum inhibitory concentration targets. Heterogeneity in model systems and pharmacodynamic endpoints is common, and models generally use intravenous ß-lactams. One-size-fits-all pharmacodynamic targets are used for regimen planning despite complexity in drug-pathogen-disease combinations. We present solutions to enable the development of global evidence-based antibiotic dosing guidance that provides adequate treatment in the context of the increasing prevalence of antimicrobial resistance and, moreover, minimizes the emergence of resistance.

Targeting the Interleukin 23 Pathway in Inflammatory Bowel Disease.

Interleukin (IL) 23, a member of the IL12 family of cytokines, maintains intestinal homeostasis, but is also implicated in the pathogenesis of inflammatory bowel diseases (IBDs). IL23 is a heterodimer composed of disulfide-linked p19 and p40 subunits. Humanized monoclonal antibodies selectively targeting the p19 subunit of IL23 are poised to become prominent drugs in IBDs. In this review, we discuss the pharmacodynamic and pharmacokinetic properties of the currently available IL23p19 inhibitors and discuss the mechanistic underpinnings of their therapeutic effects, including the mechanism of action, epitope affinity, potency, and downstream signaling. Furthermore, we address available data on the efficacy, safety, and tolerability of IL23p19 inhibitors in the treatment of IBDs and discuss important studies performed in other immune-mediated inflammatory diseases. Finally, we evaluate the potential for combining classes of biological therapies and provide future directions on the development of precision medicine-guided positioning of IL23p19 inhibitors in IBD.

Implementing differentially pigmented skin models for predicting drug response variability across human ancestries.

Persistent racial disparities in health outcomes have catalyzed legislative reforms and heightened scientific focus recently. However, despite the well-documented properties of skin pigments in binding drug compounds, their impact on therapeutic efficacy and adverse drug responses remains insufficiently explored. This perspective examines the intricate relationships between variation in melanin-based skin pigmentation and pharmacokinetics and -dynamics, highlighting the need for considering diversity in skin pigmentation as a variable to advance the equitability of pharmacological interventions. The article provides guidelines on the selection of New Approach Methods (NAMs) to foster inclusive study designs in preclinical drug development pipelines, leading to an improved level of translatability to the clinic.

Preclinical studies of gene replacement therapy for CDKL5 deficiency disorder.

Cyclin-dependent kinase-like 5 (CDKL5) deficiency disorder (CDD) is a rare neurodevelopmental disorder caused by a mutation in the X-linked CDKL5 gene. CDKL5 is a serine/threonine kinase that is critical for axon outgrowth and dendritic morphogenesis as well as synapse formation, maturation, and maintenance. This disorder is characterized by early-onset epilepsy, hypotonia, and failure to reach cognitive and motor developmental milestones. Because the disease is monogenic, delivery of the CDKL5 gene to the brain of patients should provide clinical benefit. To this end, we designed a gene therapy vector, adeno-associated virus (AAV)9.Syn.hCDKL5, in which human CDKL5 gene expression is driven by the synapsin promoter. In biodistribution studies conducted in mice, intracerebroventricular (i.c.v.) injection resulted in broader, more optimal biodistribution than did intra-cisterna magna (i.c.m.) delivery. AAV9.Syn.hCDKL5 treatment increased phosphorylation of EB2, a bona fide CDKL5 substrate, demonstrating biological activity in vivo. Our data provide proof of concept that i.c.v. delivery of AAV9.Syn.hCDKL5 to neonatal male Cdkl5 knockout mice reduces pathology and reduces aberrant behavior. Functional improvements were seen at doses of 3e11 to 5e11 vector genomes/g brain, which resulted in transfection of ≥50% of the neurons. Functional improvements were not seen at lower doses, suggesting a requirement for broad distribution for efficacy.

Cavitation-on-a-Chip Enabled Size-Specific Liposomal Drugs for Selective Pharmacokinetics and Pharmacodynamics.

The size of liposomal drugs has been demonstrated to strongly correlate with their pharmacokinetics and pharmacodynamics. While the microfluidic method successfully achieves the production of liposomes with well-controlled sizes across various buffer/lipid flow rate ratio (FRR) settings, any adjustments to the FRR inevitably influence the concentration, encapsulation efficiency (EE), and stability of liposomal drugs. Here we describe a controllable cavitation-on-a-chip (CCC) strategy that facilitates the precise regulation of liposomal drug size at any desired FRR. The CCC-enabled size-specific liposomes exhibited striking differences in uptake and biodistribution behaviors, thereby demonstrating distinct antitumor efficacy in both tumor-bearing animal and melanoma patient-derived organoid (PDO) models. Intriguingly, as the liposome size decreased to approximately 80 nm, the preferential accumulation of liposomal drugs in the liver transitioned to a predominant enrichment in the kidneys. These findings underscore the considerable potential of our CCC approach in influencing the pharmacokinetics and pharmacodynamics of liposomal nanomedicines.

Tenofovir Douche as HIV Preexposure Prophylaxis for Receptive Anal Intercourse: Safety, Acceptability, Pharmacokinetics, and Pharmacodynamics (DREAM 01).

BACKGROUND: Despite highly effective HIV preexposure prophylaxis (PrEP) options, no options provide on-demand, nonsystemic, behaviorally congruent PrEP that many desire. A tenofovir-medicated rectal douche before receptive anal intercourse may provide this option. METHODS: Three tenofovir rectal douches-220 mg iso-osmolar product A, 660 mg iso-osmolar product B, and 660 mg hypo-osmolar product C-were studied in 21 HIV-negative men who have sex with men. We sampled blood and colorectal tissue to assess safety, acceptability, pharmacokinetics, and pharmacodynamics. RESULTS: The douches had high acceptability without toxicity. Median plasma tenofovir peak concentrations for all products were several-fold below trough concentrations associated with oral tenofovir disoproxil fumarate (TDF). Median colon tissue mucosal mononuclear cell (MMC) tenofovir-diphosphate concentrations exceeded target concentrations from 1 hour through 3 to 7 days after dosing. For 6-7 days after a single product C dose, MMC tenofovir-diphosphate exceeded concentrations expected with steady-state oral TDF 300 mg on-demand 2-1-1 dosing. Compared to predrug baseline, HIV replication after ex vivo colon tissue HIV challenge demonstrated a concentration-response relationship with 1.9 log10 maximal effect. CONCLUSIONS: All 3 tenofovir douches achieved tissue tenofovir-diphosphate concentrations and colorectal antiviral effect exceeding oral TDF and with lower systemic tenofovir. Tenofovir douches may provide a single-dose, on-demand, behaviorally congruent PrEP option, and warrant continued development. Clinical Trials Registration . NCT02750540.

Defining Optimal Doses of Liposomal Amphotericin B Against Candida auris: Data From an In Vitro Pharmacokinetic/Pharmacodynamic Model.

BACKGROUND: Candida auris isolates exhibit elevated amphotericin B (AMB) minimum inhibitory concentrations (MICs). As liposomal AMB (L-AMB) can be safely administered at high doses, we explored L-AMB pharmacodynamics against C. auris isolates in an in vitro pharmacokinetic/pharmacodynamic (PK/PD) dilution model. METHODS: Four C. auris isolates with Clinical and Laboratory Standards Institute (CLSI) AMB MICs = 0.5-2 mg/L were tested in an in vitro PK/PD model simulating L-AMB pharmacokinetics. The in vitro model was validated using a Candida albicans isolate tested in animals. The peak concentration (Cmax)/MIC versus log10 colony-forming units (CFU)/mL reduction from the initial inoculum was analyzed with the sigmoidal model with variable slope (Emax model). Monte Carlo analysis was performed for the standard (3 mg/kg) and higher (5 mg/kg) L-AMB doses. RESULTS: The in vitro PK/PD relationship Cmax/MIC versus log10 CFU/mL reduction followed a sigmoidal pattern (R2 = 0.91 for C. albicans, R2 = 0.86 for C. auris). The Cmax/MIC associated with stasis was 2.1 for C. albicans and 9 for C. auris. The probability of target attainment was >95% with 3 mg/kg for wild-type C. albicans isolates with MIC ≤2 mg/L and C. auris isolates with MIC ≤1 mg/L whereas 5 mg/kg L-AMB is needed for C. auris isolates with MIC 2 mg/L. CONCLUSIONS: L-AMB was 4-fold less active against C. auris than C. albicans. Candida auris isolates with CLSI MIC 2 mg/L would require a higher L-AMB dose.

Twice-Daily Dolutegravir Based Antiretroviral Therapy with One Month of Daily Rifapentine and Isoniazid (1HP) for TB Prevention.

BACKGROUND: One month of daily rifapentine + isoniazid (1HP) is an effective, ultrashort option for TB prevention in people with HIV (PWH). However, rifapentine may decrease antiretroviral drug concentrations and increase the risk of virologic failure. ACTG A5372 evaluated the effect of 1HP on the pharmacokinetics of twice daily dolutegravir. METHODS: A5372 was a multicenter, pharmacokinetic study in PWH (≥18 years) already on dolutegravir-containing antiretroviral therapy with HIV RNA < 50 copies/mL. Participants received daily rifapentine/isoniazid (600mg/300mg) for 28 days as part of 1HP. Dolutegravir was increased to 50mg twice daily during 1HP and intensive pharmacokinetic sampling was performed on day 0 (before 1HP) and on the final day of 1HP treatment. RESULTS: Thirty-two participants (41% female; 66% Black/African; median (Q1, Q3) age 42 (34, 49) years) were included in the pharmacokinetic analysis. Thirty-one of 32 had HIV RNA levels <50 copies/mL at the end of 1HP dosing. One participant had an HIV RNA of 160 copies/mL at day 28, with HIV RNA <50 copies/mL upon repeat testing on day 42. The median (Q1, Q3) dolutegravir trough concentration was 1751 ng/mL (1195, 2542) on day 0 vs. 1987ng/mL (1331, 2278) on day 28 (day 28:day 0 GMR 1.05, [90% CI 0.93-1.2]; p = 0.43). No serious adverse events were reported. CONCLUSION: Dolutegravir trough concentrations with 50mg twice daily dosing during 1HP treatment were greater than those with standard dose dolutegravir once daily without 1HP. These pharmacokinetic, virologic, and safety data provide support for twice daily dolutegravir use in combination with 1HP for TB prevention.

Amoxicillin-Clavulanate Breakpoints Against Enterobacterales: Rationale for Revision by the Clinical and Laboratory Standards Institute.

Amoxicillin-clavulanate (AMC) is among the most frequently prescribed antibiotics globally. It has broad antibacterial activity against gram-positive, gram-negative, and anaerobic bacteria and has been used to treat infections caused by a broad range of pathogens. AMC breakpoints against Enterobacterales were initially set in the 1980s. However, since that time, increases in antibiotic resistance, advances in pharmacokinetic/pharmacodynamic analyses, and publication of additional clinical data prompted a reassessment by the Clinical and Laboratory Standards Institute (CLSI) Subcommittee on Antimicrobial Susceptibility Testing. Based on this contemporary reappraisal, the CLSI retained the Enterobacterales breakpoints but revised comments regarding dosing associated with use of the AMC breakpoints in the 2022 supplement of M100. This viewpoint provides insight into the CLSI breakpoint reevaluation process and summarizes the data and rationale used to support these revisions to the AMC Enterobacterales breakpoint.

Translational modeling-based evidence for enhanced efficacy of standard-of-care drugs in combination with anti-microRNA-155 in non-small-cell lung cancer.

BACKGROUND: Elevated microRNA-155 (miR-155) expression in non-small-cell lung cancer (NSCLC) promotes cisplatin resistance and negatively impacts treatment outcomes. However, miR-155 can also boost anti-tumor immunity by suppressing PD-L1 expression. Therapeutic targeting of miR-155 through its antagonist, anti-miR-155, has proven challenging due to its dual molecular effects. METHODS: We developed a multiscale mechanistic model, calibrated with in vivo data and then extrapolated to humans, to investigate the therapeutic effects of nanoparticle-delivered anti-miR-155 in NSCLC, alone or in combination with standard-of-care drugs. RESULTS: Model simulations and analyses of the clinical scenario revealed that monotherapy with anti-miR-155 at a dose of 2.5 mg/kg administered once every three weeks has substantial anti-cancer activity. It led to a median progression-free survival (PFS) of 6.7 months, which compared favorably to cisplatin and immune checkpoint inhibitors. Further, we explored the combinations of anti-miR-155 with standard-of-care drugs, and found strongly synergistic two- and three-drug combinations. A three-drug combination of anti-miR-155, cisplatin, and pembrolizumab resulted in a median PFS of 13.1 months, while a two-drug combination of anti-miR-155 and cisplatin resulted in a median PFS of 11.3 months, which emerged as a more practical option due to its simple design and cost-effectiveness. Our analyses also provided valuable insights into unfavorable dose ratios for drug combinations, highlighting the need for optimizing dose regimens to prevent antagonistic effects. CONCLUSIONS: This work bridges the gap between preclinical development and clinical translation of anti-miR-155 and unravels the potential of anti-miR-155 combination therapies in NSCLC.

Development of New Tuberculosis Drugs: Translation to Regimen Composition for Drug-Sensitive and Multidrug-Resistant Tuberculosis.

Tuberculosis (TB) kills more people than any other infectious disease. Challenges for developing better treatments include the complex pathology due to within-host immune dynamics, interpatient variability in disease severity and drug pharmacokinetics-pharmacodynamics (PK-PD), and the growing emergence of resistance. Model-informed drug development using quantitative and translational pharmacology has become increasingly recognized as a method capable of drug prioritization and regimen optimization to efficiently progress compounds through TB drug development phases. In this review, we examine translational models and tools, including plasma PK scaling, site-of-disease lesion PK, host-immune and bacteria interplay, combination PK-PD models of multidrug regimens, resistance formation, and integration of data across nonclinical and clinical phases.We propose a workflow that integrates these tools with computational platforms to identify drug combinations that have the potential to accelerate sterilization, reduce relapse rates, and limit the emergence of resistance.

In vivo dose response and efficacy of the ß-lactamase inhibitor, durlobactam, in combination with sulbactam against the Acinetobacter baumannii-calcoaceticus complex.

Multi-drug resistant (MDR) Acinetobacter baumannii is emerging as a pathogen of increasing prevalence and concern. Infections associated with this Gram-negative pathogen are often associated with increased morbidity and mortality and few therapeutic options. The ß-lactamase inhibitor sulbactam used commonly in combination with ampicillin demonstrates intrinsic antibacterial activity against A. baumannii acting as an inhibitor of PBP1 and PBP3, which participate in cell wall biosynthesis. The production of ß-lactamases, particularly class D oxacillinases, however, has limited the utility of sulbactam resorting to increased doses and the need for alternate therapies. Durlobactam is a non-ß-lactam ß-lactamase inhibitor that demonstrates broad ß-lactamase inhibition including class D enzymes produced by A. baumannii and has shown potent in vitro activity against MDR A. baumannii, particularly carbapenem-resistant isolates in susceptibility and pharmacodynamic model systems. The objective of this study is to evaluate the exposure-response relationship of sulbactam and durlobactam in combination using in vivo neutropenic thigh and lung models to establish PK/PD exposure magnitudes to project clinically effective doses. Utilizing established PK/PD determinants of %T>MIC and AUC/MIC for sulbactam and durlobactam, respectively, non-linear regressional analysis of drug exposure was evaluated relative to the 24-hour change in bacterial burden (log10 CFU/g). Co-modeling of the data across multiple strains exhibiting a broad range of MIC susceptibility suggested net 1-log10 CFU/g0 reduction can be achieved when sulbactam T>MIC exceeds 50% of the dosing interval and durlobactam AUC/MIC is 10. These data were ultimately used to support sulbactam-durlobactam dose selection for Phase 3 clinical trials.

I n vitro pharmacokinetics/pharmacodynamics of the ß-lactamase inhibitor, durlobactam, in combination with sulbactam against Acinetobacter baumannii-calcoaceticus complex.

Infections caused by Acinetobacter baumannii are increasingly multidrug resistant and associated with high rates of morbidity and mortality. Sulbactam is a ß-lactamase inhibitor with intrinsic antibacterial activity against A. baumannii. Durlobactam is a non-ß-lactam ß-lactamase inhibitor with an extended spectrum of activity compared to other inhibitors of its class. In vitro pharmacodynamic infection models were undertaken to establish the pharmacokinetic/pharmacodynamic (PK/PD) index and magnitudes associated with sulbactam and durlobactam efficacy and to simulate epithelial lining fluid (ELF) exposures at clinical doses to understand sulbactam-durlobactam activity with and without co-administration of a carbapenem. Hollow fiber infection models (HFIMs) and one-compartment systems were used to identify the PK/PD indices and exposure magnitudes associated of 1-log10 and 2-log10 colony-forming unit (CFU)/mL reductions. Sulbactam and durlobactam demonstrated PK/PD drivers of % time above the minimum inhibition concentration (%T > MIC) and area under the plasma concentration-time curve from time 0 to 24 h (AUC0-24)/MIC, respectively. Against a sulbactam-susceptible strain, sulbactam %T > MIC of 71.5 and 82.0 were associated with 1-log10 and 2-log10 CFU/mL reductions, respectively, in the HFIM. Against a non-susceptible strain, durlobactam restored the activity of sulbactam with an AUC0-24/MICs of 34.0 and 46.8 using a polysulfone cartridge to achieve a 1-log10 and 2-log10 CFU/mL reduction. These magnitudes were reduced to 13.8 and 24.2, respectively, using a polyvinylidene fluoride cartridge with a membrane pore size of 0.1 µm. In the one-compartment model, durlobactam AUC0-24/MIC to achieve 1-log10 and 2-log10 CFU/mL reduction were 7.6 and 33.4, respectively. Simulations of clinical ELF exposures in the HFIM showed cidal activity at MICs ≤4 µg/mL. Penicillin binding protein 3 mutant strains with MICs of 8 µg/mL may benefit from the addition of a carbapenem at clinical exposures.

Updated antimicrobial dosing recommendations for obese patients.

The prevalence of obesity has increased considerably in the last few decades. Pathophysiological changes in obese patients lead to pharmacokinetic (PK) and pharmacodynamic (PD) alterations that can condition the correct exposure to antimicrobials if standard dosages are used. Inadequate dosing in obese patients can lead to toxicity or therapeutic failure. In recent years, additional antimicrobial PK/PD data, extended infusion strategies, and studies in critically ill patients have made it possible to obtain data to provide a better dosage in obese patients. Despite this, it is usually difficult to find information on drug dosing in this population, which is sometimes contradictory. This is a comprehensive review of the dosing of different types of antimicrobials (antibiotics, antifungals, antivirals, and antituberculosis drugs) in obese patients, where the literature on PK and possible dosing strategies in obese adults was critically assessed.

In vivo pharmacodynamic characterization of a next-generation polyene, SF001, in the invasive pulmonary aspergillosis mouse model.

SF001 is a next-generation polyene antifungal drug in development, designed to have increased specificity to fungal ergosterol, which is absent in humans, and decreased binding to cholesterol. SF001 demonstrates long-acting, potent, broad-spectrum fungicidal activity. The goal of the current study was to determine the pharmacodynamic index and target of SF001 in an immunocompromised mouse model of invasive pulmonary aspergillosis against six Aspergillus fumigatus isolates. Minimum inhibitory concentration (MIC) values ranged from 0.5 to 2.0 mg/L. Plasma and epithelial lining fluid (ELF) pharmacokinetics were performed following single intraperitoneal doses of 1, 4, 16, and 64 mg/kg. Treatment efficacy was assessed with each of the six fungal isolates using daily doses of SF001 ranging from 0.25 to 64 mg/kg/day over a 96-h treatment duration. Efficacy was assessed by A. fumigatus quantitative PCR of conidial equivalents from lung homogenates. Nonlinear regression analysis using the Hill equation demonstrated that the 24-h exposure-response relationships for both plasma and ELF area under the concentration/MIC and Cmax/MIC ratios were strong and relatively similar [coefficient of determination (R2) = 0.74-0.75). Exposure-response relationships included a median plasma 24-h Cmax/MIC target for stasis and 1-log kill endpoint of 0.5 and 0.6, respectively. The present studies demonstrated in vitro and in vivo SF001 potency against A. fumigatus. These results have potential relevance for SF001 clinical dose selection and evaluation of susceptibility breakpoints.

Balancing the scales: achieving the optimal beta-lactam to beta-lactamase inhibitor ratio with continuous infusion piperacillin/tazobactam against extended spectrum beta-lactamase producing Enterobacterales.

Piperacillin/tazobactam (TZP) is administered intravenously in a fixed ratio (8:1) with the potential for inadequate tazobactam exposure to ensure piperacillin activity against Enterobacterales. Adult patients receiving continuous infusion (CI) of TZP and therapeutic drug monitoring (TDM) of both agents were evaluated. Demographic variables and other pertinent laboratory data were collected retrospectively. A population pharmacokinetic approach was used to select the best kidney function model predictive of TZP clearance (CL). The probability of target attainment (PTA), cumulative fraction of response (CFR) and the ratio between piperacillin and tazobactam were computed to identify optimal dosage regimens by continuous infusion across kidney function. This study included 257 critically ill patients (79.3% male) with intra-abdominal, bloodstream, and hospital-acquired pneumonia infections in 89.5% as the primary indication. The median (min-max range) age, body weight, and estimated glomerular filtration rate (eGFR) were 66 (23-93) years, 75 (39-310) kg, and 79.2 (6.4-234) mL/min, respectively. Doses of up to 22.5 g/day were used to optimize TZP based on TDM. The 2021 chronic kidney disease epidemiology equation in mL/min best modeled TZP CL. The ratio of piperacillin:tazobactam increased from 6:1 to 10:1 between an eGFR of <20 mL/min and >120 mL/min. At conventional doses, the PTA is below 90% when eGFR is ≥100 mL/min. Daily doses of 18 g/day and 22.5 g/day by CI are expected to achieve a >80% CFR when eGFR is 100-120 mL/min and >120-160 mL/min, respectively. Inadequate piperacillin and tazobactam exposure is likely in patients with eGFR ≥ 100 mL/min. Dose regimen adjustments informed by TDM should be evaluated in this specific population.

Omadacycline pharmacokinetics/pharmacodynamics and efficacy against multidrug-resistant Mycobacterium tuberculosis in the hollow fiber system model.

Seventy-five years ago, first-generation tetracyclines demonstrated limited efficacy in the treatment of tuberculosis but were more toxic than efficacious. We performed a series of pharmacokinetic/pharmacodynamic (PK/PD) experiments with a potentially safer third-generation tetracycline, omadacycline, for the treatment of multidrug-resistant tuberculosis (MDR-TB). Mycobacterium tuberculosis (Mtb) H37Rv and an MDR-TB clinical strain (16D) were used in the minimum inhibitory concentration (MIC) and static concentration-response studies in test tubes, followed by a PK/PD study using the hollow fiber system model of TB (HFS-TB) that examined six human-like omadacycline doses. The inhibitory sigmoid maximal effect (Emax) model and Monte Carlo experiments (MCEs) were used for data analysis and clinical dose-finding, respectively. The omadacycline MIC for both Mtb H37Rv and MDR-TB clinical strain was 16 mg/L but dropped to 4 mg/L with daily drug supplementation to account for omadacycline degradation. The Mycobacteria Growth Indicator Tube MIC was 2 mg/L. In the test tubes, omadacycline killed 4.39 log10 CFU/mL in 7 days. On Day 28 of the HFS-TB study, the Emax was 4.64 log10 CFU/mL, while exposure mediating 50% of Emax (EC50) was an area under the concentration-time curve to MIC (AUC0-24/MIC) ratio of 22.86. This translates to PK/PD optimal exposure or EC80 as AUC0-24/MIC of 26.93. The target attainment probability of the 300-mg daily oral dose was 90% but fell at MIC ≧4 mg/L. Omadacycline demonstrated efficacy and potency against both drug-susceptible and MDR-TB. Further studies are needed to identify the omadacycline effect in combination therapy for the treatment of both drug-susceptible and MDR-TB.