Hollow Fiber System Research Articles

Personalized CZA-ATM dosing against an XDR E. coli in liver transplant patients; the application of the in vitro hollow fiber system.

A patient with an extensively drug-resistant (XDR) New Delhi metallo-β-lactamase (NDM) and oxacillinase (OXA-48) producing Escherichia coli (E. coli) infection was awaiting orthotopic liver transplant. There is no standardized antibiotic prophylaxis regimen; however, in line with the Infectious Diseases Society of America guidance, an antibiotic prophylactic regimen of ceftazidime-avibactam 2.5g TDS with aztreonam 2g three times a day (TDS) IV was proposed. The hollow fiber system (HFS) was applied to inform the individualized pharmacodynamic outcome likelihood prior to prophylaxis. A 4-log reduction in CFU/mL in the first 10 h of the regimen exposure was observed; however, the killing dynamics were slow and six 8-hourly infusions were required to reduce bacterial cells to below the limit of quantification. Thus, the HFS supported the use of the regimen for infection clearance; however, it highlighted the need for several infusions. Standard local practice is to administer prophylaxis antibiotics at induction of orthotopic liver transplantation (OLT); however, the HFS provided data to rationalize earlier dosing. Therefore, the patient was dosed at 24 h prior to their OLT induction and subsequently discharged 8 days after surgery. The HFS provides a dynamic culture solution for informing individualized medicine by testing antibiotic combinations and exposures against the bacterial isolates cultured from the patient's infection. .

Antibacterial action of penicillin against Mycobacterium avium complex.

β-lactam antibiotics are promising treatments for Mycobacterium avium complex (MAC) lung disease. We hypothesized that benzylpenicillin has efficacy against MAC. Benzylpenicillin lung concentration-time profiles of seven doses in three dosing schedules were administered for 28 days using the hollow fiber system model of intracellular MAC (HFS-MAC). Data were analyzed using the inhibitory sigmoid maximal effect (Emax) model for each sampling day, while two ordinary differential equations (ODEs) were used for the wild-type and penicillin-resistant mutants. Benzylpenicillin killed >2.1 log10 colony-forming unit (CFU)/mL below Day 0, better than azithromycin, ethambutol, and rifabutin. Efficacy was terminated by acquired resistance. Sigmoid Emax parameter estimates significantly differed between sampling days and were a poor fit. However, ODE model parameter estimates vs. exposure were a better fit. The exposure mediating Emax was 84.6% (95% CI 76.91-82.98) of time concentration exceeded the minimum inhibitory concentration (MIC). In Monte Carlo experiments, 24 million international units of benzylpenicillin continuous infusion achieved the target exposure in lungs of >90% of 10,000 subjects until an MIC of 64 mg/L, designated the susceptibility breakpoint. Benzylpenicillin demonstrated a better bactericidal effect against MAC than guideline-recommended drugs before the development of resistance. Its role in combination therapy with other drugs with better efficacy than guideline-recommended drugs should be explored.

Determining stemness and exosome production from nutrient-dependent cells: Influence of the molecular weight cut-off in hollow fiber membrane systems

This study aimed to optimize parameters for cultivating adipose-derived stem cells (ADSCs) in hollow fiber membrane systems. Enhanced ADSC cultivation was achieved in this study by utilizing a higher cell seeding rate (10 mL/min) and fibronectin coating (8 μg/cm²) on the membrane. A pulsatile flow perfusion (30 min on / 3 h off) for 24 h, followed by continuous flow perfusion at a lower rate (<20 mL/min), was employed. Notably, a two-day medium change maintained CD73 expression (79.26 %) compared to scenarios without changes (1.92 %) over eight days. Using a membrane cut-off of 20 kDa and <0.1 μm, a 1.4- and 2.8-fold increase in proliferated cells was observed; however, CD73 expression decreased by 10.07 and 33.63 %, respectively. The membrane with a pore size of <0.1 μm exhibited 1.4-fold higher exosome particle numbers. In conclusion, nutrient supplementation emerged as crucial for optimal ADSC cultivation in hollow fiber systems.

Mixed Matrix Pt-Carbon Nanofiber Polyethersulfone Catalytic Membranes for Glucose Dehydrogenation.

The advancement of technologies for producing chemicals and materials from non-fossil resources is of critical importance. An illustrative example is the dehydrogenation of glucose, to yield gluconic acid, a specialty chemical. In this study, we propose an innovative production route for gluconic acid while generating H2 as a co-product. Our concept involves a dual-function membrane, serving both as a catalyst for glucose dehydrogenation into gluconic acid and as a means to efficiently remove the produced H2 from the reaction mixture. To achieve this two membranes were developed, one catalytically active and one dense aimed at H2 removal. The catalytic membrane showed significant activity, yielding 16 % gluconic acid (t=120 min) with a catalyst selectivity of 93 % and stable performance over five consecutive cycles. Incorporating the H2 separating membrane showed the significance of H2 removal in driving the reaction forward. Its inclusion led to a twofold increase in gluconic acid yield, aligning with Le Chatelier's principles. As a future prospect the two layers can be combined into a dual-layer membrane which opens the way for a new production route to simultaneously produce gluconic acid and H2, using high-throughput reactors such as hollow-fiber systems.

Ertapenem's therapeutic potential for Mycobacterium avium lung disease in the hollow fibre model

IntroductionGuideline-based therapy for Mycobacterium avium complex (MAC) pulmonary disease achieves sustained sputum conversion rates in only 43–53% of patients. Repurposing of β-lactam antibiotics such as ertapenem could expedite design of more efficacious regimens, compared to developing new drugs. MethodsWe performed an ertapenem exposure-response study in the hollow fibre system model of intracellular MAC (HFS-MAC). We recapitulated human-like intrapulmonary concentration-time profiles of eight once-daily intravenous doses of ertapenem over 28 days and performed repetitive sampling for drug concentration-time profiles and MAC burden. The % of time concentration persisted above MIC (%TMIC) mediating either 50% or 80% of maximal effect (E50, EC80) were identified. The EC80 was used as target exposure in a 10 000 subject Monte Carlo experiments for ertapenem doses of 1G, 2G, or 4G administered once versus twice daily. ResultsThe ertapenem MIC ranged from 0.5 to 2 mg/L on three occasions. Ertapenem achieved a half-life of 4.04 ± 0.80 h in the HFS-MAC and killed a maximum of 2.17 log10 CFU/mL below day 0. The EC50 was %TMIC of 75.9% (95% confidence interval: 68.43%–86.54%) and the EC80 was %TMIC of 100%. Target attainment probability was >90% for 1G twice daily up to an MIC of 2 mg/L, while for 2G twice daily the susceptibility MIC breakpoint was 4–8 mg/L. ConclusionsErtapenem microbial kill below day 0 burden was better than guideline-based therapy drugs in the HFS-MAC in the past. Ertapenem is a promising drug for novel combination therapies for MAC lung disease.

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.

Ceftriaxone Efficacy for Mycobacterium avium Complex Lung Disease in the Hollow Fiber and Translation to Sustained Sputum Culture Conversion in Patients.

Only 35.6%-50.8% of patients with Mycobacterium avium complex (MAC) pulmonary disease achieve sustained sputum culture conversion (SSCC) on treatment with the azithromycin-ethambutol-rifabutin standard of care (SOC). We tested the efficacy of ceftriaxone, a β-lactam with a lung-to-serum penetration ratio of 12.18-fold. We mimicked lung concentration-time profiles of 7 ceftriaxone once-daily doses for 28 days in the hollow fiber system model of intracellular MAC (HFS-MAC). Monte Carlo experiments were used for dose selection. We also compared once-daily ceftriaxone monotherapy to 3-drug SOC against 5 MAC clinical isolates in HFS-MAC using γ (kill) slopes, and translated to SSCC rates. Ceftriaxone killed 1.02-3.82 log10 colony-forming units (CFU)/mL, at optimal dose of 2 g once-daily. Ceftriaxone killed all 5 strains below day 0 versus 2 of 5 for SOC. The median γ (95% confidence interval [CI]) was 0.49 (.47-.52) log10 CFU/mL/day for ceftriaxone and 0.38 (.34-.43) log10 CFU/mL/day for SOC. In patients, the SOC was predicted to achieve SSCC rates (CI) of 39.3% (36%-42%) at 6 months. The SOC SSCC was 50% at 8.18 (3.64-27.66) months versus 3.58 (2.20-7.23) months for ceftriaxone, shortening time to SSCC 2.35-fold. Ceftriaxone is a promising agent for creation of short-course chemotherapy.

Sarecycline pharmacokinetics/pharmacodynamics in the hollow-fibre model of Mycobacterium avium complex: so near and yet so far.

Poor sustained sputum culture conversion rates with the standard-of-care therapy highlight the need for better drugs to treat Mycobacterium avium complex pulmonary disease (MAC-PD). To determine the pharmacokinetics/pharmacodynamics (PK/PD)-optimized exposure of sarecycline and its potential role in treating MAC-PD. We performed MIC studies with MAC ATCC 700898 and 19 clinical isolates and test-tube static concentration-response studies. A dynamic hollow-fibre system model of intracellular MAC (HFS-MAC) study was performed mimicking six human-equivalent sarecycline dose concentration-time profiles to identify the PK/PD optimal exposure of sarecycline for MAC kill. The inhibitory sigmoid maximal effect (Emax) model was used for PK/PD analysis. The sarecycline MIC of MAC ATCC 700898 was 1 mg/L, while the MIC for the 19 clinical strains ranged between 32 and >256 mg/L. The concentration mediating 50% of Emax (EC50) was similar between intracellular and extracellular MAC. In the HFS-MAC, all six sarecycline doses killed intracellular MAC, with an Emax of 1.0 log10 cfu/mL below Day 0 burden (stasis). The sarecycline EC80 (optimal) exposure was identified as AUC0-24/MIC = 139.46. Sarecycline demonstrated anti-MAC Emax in the HFS-MAC model better than ethambutol but worse than omadacycline (>5 log10 cfu/mL below stasis) in HFS-MAC. However, since currently approved highest oral sarecycline dose achieves an AUC0-24 of 48.2 mg·h/L and MAC MICs are >32 mg/L, the target AUC0-24/MIC of 139.46 is unlikely to be achieved in patients.

Polyphenol-coated hollow fiber system for energy-efficient dehumidification in air-conditioning

Increasing temperatures have worldwide become a high health risk. High humidity aggravates the risk and reduces the comfort perception. Conventional air conditioners produce annually the equivalent of 2150 million carbon dioxide tons per year. Dehumidification is responsible for a large portion of it. Membrane-based dehumidification is energy-efficient since water vapor removal is carried out at isothermal conditions without toxic materials. This work demonstrates a membrane dehumidification system based on industry-ready prototypes containing polymeric hollow fibers coated with a green polyphenol coating, showcasing/exhibiting a remarkable water vapor transport rate with selectivity. Long-term testing proved over a year of operation with only a minimal decline in vapor transport. And the proposed system has 4–5 times higher coefficient of performance (COP) than conventional dehumidifiers, and it is a highly competitive energy-saving device with a low contribution to emissions and a smaller footprint.

In vitro model to simulate multiple drugs with distinct elimination half-lives

The prevalence of drug resistance in pathogens such as HIV and selected bacteria has been steadily rising, resulting in an increased need for using multiple agents concurrently. Agents used in these combination therapies may have different elimination half-lives in humans. There is an unmet need for in vitro models to evaluate the efficacy of these combinations to guide early drug development. In order to realistically reflect in vivo conditions, useful in vitro model systems must be capable of simulating multiple pharmacokinetic profiles with distinct elimination half-lives. The goal of this study was to experimentally simulate four pharmacokinetic profiles with distinct elimination half-lives in an in vitro hollow-fibre system. For illustrative purposes, fluctuating exposures of ceftriaxone were simulated with distinct half-lives of 1, 2.5, 8, and 12 hours. A parallel experimental setup was used to independently connect four supplemental reservoirs to a central reservoir. Target maximum concentration was achieved by direct drug dosing into the central reservoir; supplemental reservoirs were also dosed to offset the rapid drug elimination rate from the central reservoir. Serial pharmacokinetic samples were obtained from the central reservoir, assayed by a spectrophotometric method, and characterized by a one-compartment model. The observed maximum concentrations and elimination half-lives were in agreement with the expected values obtained from the mathematical predictions. This in vitro experimental system can be used to evaluate the efficacy of up to four-drug combinations against multidrug-resistant bacteria or HIV-infected mammalian cells. The established framework represents an adaptable tool to advance the field of combination therapy.

Rapid In Vitro Assessment of Antimicrobial Drug Effect Bridging Clinically Relevant Pharmacokinetics: A Comprehensive Methodology.

Rapid in vitro assessment of antimicrobial drug efficacy under clinically relevant pharmacokinetic conditions is an essential element of both drug development and clinical use. Here, we present a comprehensive overview of a recently developed novel integrated methodology for rapid assessment of such efficacy, particularly against the emergence of resistant bacterial strains, as jointly researched by the authors in recent years. This methodology enables rapid in vitro assessment of the antimicrobial efficacy of single or multiple drugs in combination, following clinically relevant pharmacokinetics. The proposed methodology entails (a) the automated collection of longitudinal time-kill data in an optical-density instrument; (b) the processing of collected time-kill data with the aid of a mathematical model to determine optimal dosing regimens under clinically relevant pharmacokinetics for single or multiple drugs; and (c) in vitro validation of promising dosing regimens in a hollow fiber system. Proof-of-concept of this methodology through a number of in vitro studies is discussed. Future directions for the refinement of optimal data collection and processing are discussed.

Tension controlled hollow-fiber winding machine for blood oxygenator prototypes

Blood oxygenators involve a complex network of hollow fibers for efficient gas exchange with blood. The optimal microstructural arrangement of these fibers is an ongoing research interest. While the fiber systems of commercial oxygenators are manufactured to address mass production, the research oxygenator prototypes demand more flexibility so that different design parameters can be tested. Here a hollow-fiber assembly system is designed and built for winding research grade extracorporeal blood oxygenator mandrels at different layout dimensions so that these different configurations can be evaluated for mass transfer capacity and blood damage. The hardware design and manufacturing details of this system presented together with its impact on the prototype oxygenator device assembly process. This in-house built system can wind thin fibers, having outer diameters ranging from 100 μm to 1 mm, at any specified winding angle continuously. A control system for fiber stress is also incorporated to eliminate fiber damage. Our system consists of three main units: (1) unwinding, (2) accumulator, and (3) winding systems, integrated together via the control software. The unwinding unit has a PID controller to maintain the position of the accumulator motor on the reference point by tuning the velocity of feeding fibers to the accumulator unit. Another PID controller preserves the desired tension value of the fibers by adjusting the position of the accumulator motor. Desired tension value is defined by the user and typically obtained through uniaxial testing of fibers. The control unit employs a “cascaded” PID controller since the PID controller in the accumulator unit maintains the tension and the PID controller in the unwinding unit controls the position of the accumulator motor. Finally, the winding unit utilizes two motors to wind the fibers over the outer diameter of a mandrel at the desired winding angle. The first motor drives the translational movement, and the second one provides mandrel rotation. The desired angles are achieved by tuning the synchronous movement of the winding motors. While the system is designed to produce assembled blood oxygenator mandrel prototypes, this concept is also applicable for producing cylindrical fiber-reinforced composite materials with specified fiber angles and stents winded on jigs.

Omadacycline pharmacokinetics/pharmacodynamics in the hollow fiber model and clinical validation of efficacy to treat pulmonary Mycobacterium abscessus disease

BackgroundGuideline-based therapy (GBT) for pulmonary Mycobacterium abscessus (Mab) disease achieves sustained sputum culture conversion (SSCC) rates of 30%; this is reflected by poor efficacy of GBT in the hollow fiber system model of Mab (HFS-Mab), which killed ∼1.22 log10 CFU/mL. This study was performed to determine which clinical dose of omadacycline, a tetracycline antibiotic, should be used in combination therapy to treat pulmonary Mab disease for relapse-free cure. MethodsFirst, omadacycline intrapulmonary concentration-time profiles of seven daily doses were mimicked in the HFS-Mab model and exposures associated with optimal efficacy were identified. Second, 10,000 subject Monte-Carlo simulations were performed to determine whether oral omadacycline 300 mg/day achieved these optimal exposures. Third, a retrospective clinical study on omadacycline vs. primarily tigecycline-based salvage therapy was conducted to assess rates of SSCC and toxicity. Fourth, a single patient was recruited to validate the findings. ResultsOmadacycline efficacy in the HFS-Mab was 2.09 log10 CFU/mL at exposures achieved in >99% of patients on 300 mg/day omadacycline. In the retrospective study of omadacycline 300 mg/day-based combinations vs. comparators, SSCC was achieved in 8/10 vs. 1/9 (P=0.006), symptom improvement in 8/8 vs. 5/9 (P=0.033), toxicity in 0 vs. 9/9 (P<0.001), and therapy discontinuation due to toxicity in 0 vs. 3/9 (P<0.001) cases, respectively. In one prospectively recruited patient, omadacycline 300 mg/day salvage therapy achieved SSCC and symptom-resolution in 3 months. ConclusionBased on the preclinical and clinical data, omadacycline 300 mg/day in combination regimens could be appropriate for testing in Phase III trials in patients with Mab pulmonary disease.

Hollow-fibre system model of tuberculosis reproducibility and performance specifications for best practice in drug and combination therapy development.

The hollow-fibre system model of tuberculosis (HFS-TB) has been endorsed by regulators; however, application of HFS-TB requires a thorough understanding of intra- and inter-team variability, statistical power and quality controls. Three teams evaluated regimens matching those in the Rapid Evaluation of Moxifloxacin in Tuberculosis (REMoxTB) study, plus two high-dose rifampicin/pyrazinamide/moxifloxacin regimens, administered daily for up to 28 or 56 days against Mycobacterium tuberculosis (Mtb) under log-phase growth, intracellular growth or semidormant growth under acidic conditions. Target inoculum and pharmacokinetic parameters were pre-specified, and the accuracy and bias at achieving these calculated using percent coefficient of variation (%CV) at each sampling point and two-way analysis of variance (ANOVA). A total of 10 530 individual drug concentrations, and 1026 individual cfu counts were measured. The accuracy in achieving intended inoculum was >98%, and >88% for pharmacokinetic exposures. The 95% CI for the bias crossed zero in all cases. ANOVA revealed that the team effect accounted for <1% of variation in log10 cfu/mL at each timepoint. The %CV in kill slopes for each regimen and different Mtb metabolic populations was 5.10% (95% CI: 3.36%-6.85%). All REMoxTB arms exhibited nearly identical kill slopes whereas high dose regimens were 33% faster. Sample size analysis revealed that at least three replicate HFS-TB units are needed to identify >20% difference in slope, with a power of >99%. HFS-TB is a highly tractable tool for choosing combination regimens with little variability between teams, and between replicates.

Population pharmacokinetics and dose evaluations of linezolid in the treatment of multidrug-resistant tuberculosis.

Background: The pharmacokinetic/pharmacodynamics (PK/PD) target derived from the hollow-fiber system model for linezolid for treatment of the multidrug-resistant tuberculosis (MDR-TB) requires clinical validation. Therefore, this study aimed to develop a population PK model for linezolid when administered as part of a standardized treatment regimen, to identify the PK/PD threshold associated with successful treatment outcomes and to evaluate currently recommended linezolid doses. Method: This prospective multi-center cohort study of participants with laboratory-confirmed MDR-TB was conducted in five TB designated hospitals. The population PK model for linezolid was built using nonlinear mixed-effects modeling using data from 168 participants. Boosted classification and regression tree analyses (CART) were used to identify the ratio of 0- to 24-h area under the concentration-time curve (AUC0-24h) to the minimal inhibitory concentration (MIC) threshold using the BACTEC MGIT 960 method associated with successful treatment outcome and validated in multivariate analysis using data from a different and prospective cohort of 159 participants with MDR-TB. Furthermore, based on the identified thresholds, the recommended doses were evaluated by the probability of target attainment (PTA) analysis. Result: Linezolid plasma concentrations (1008 samples) from 168 subjects treated with linezolid, were best described by a 2-compartment model with first-order absorption and elimination. An AUC0-24h/MIC > 125 was identified as a threshold for successful treatment outcome. Median time to sputum culture conversion between the group with AUC0-24h/MIC above and below 125 was 2 versus 24months; adjusted hazard ratio (aHR), 21.7; 95% confidence interval (CI), (6.4, 72.8). The boosted CART-derived threshold and its relevance to the final treatment outcome was comparable to the previously suggested target of AUC0-24h/MIC (119) using MGIT MICs in a hollow fiber infection model. Based on the threshold from the present study, at a standard linezolid dose of 600mg daily, PTA was simulated to achieve 100% at MGIT MICs of ≤ .25mg which included the majority (81.1%) of isolates in the study. Conclusion: We validated an AUC0-24h/MIC threshold which may serve as a target for dose adjustment to improve efficacy of linezolid in a bedaquiline-containing treatment. Linezolid exposures with the WHO-recommended dose (600mg daily) was sufficient for all the M. tb isolates with MIC ≤ .25mg/L.

Humidification Performance Evaluation of hollow-fiber membrane-based humidifier for air-conditioning

Indoor viral and fungal activity is affected by the concentration of moisture in the air. Since the concentration of viruses and fungi in the air directly affects the human body, it is necessary to maintain a specific humidity range through the air-conditioning system. The optimum humidity in the building is 40-60%, and it needs to be maintained regardless of the season. In winter, a separate humidification system is required to adjust the indoor humidity due to the dry outside air. However, since the conventional humidification system injects water or steam directly into the air, various problems, such as water pollution, occur. Therefore, this study proposed a new humidification method called the hollow-fiber membrane humidification system to increase indoor humidity, and the effect was experimentally evaluated. When 150 CMH (air volume of ventilation level) was supplied, the absolute humidity increased by about 4.14g/kg compared to the initial condition, and the relative humidity of the indoor supply air increased to about 64%.

1698. Pharmacokinetics/pharmacodynamics of Epetraborole, a Novel Bacterial Leucyl-tRNA Synthetase Inhibitor, and High Intracellular Penetration in the Intracellular Hollow Fiber System Model of Mycobacterium avium Complex Lung Disease

Abstract Background Epetraborole (EBO) is a boron-containing, oral inhibitor of bacterial leucyl-tRNA synthetase, an essential enzyme in protein synthesis; EBO demonstrates potent activity against nontuberculous mycobacteria. Dose-effect studies in the intracellular hollow fiber system model of Mycobacterium avium complex (MAC) lung disease, or HFS-MAC, have demonstrated that EBO is highly bactericidal. In this study we used dose fractionation in the HFS-MAC system to find the best pharmacokinetic/ pharmacodynamic (PK/PD) index that was associated with EBO microbial kill and acquired microbial resistance (AMR). Methods A dose-fractionation design was used to dose 30 HFS-MAC units. ED20, ED50 and ED80 doses were administered as one of 4 dose schedules of twice daily, once daily, twice weekly, or once weekly at a half-life of 10.4h. Total MAC burden and EBO-resistant MAC burden were determined every 7 days by culturing HFS-MAC contents on Middlebrook 7H10 agar. For drug concentrations, the central compartment of each HFS-MAC unit was sampled throughout the 28 days, and after the final dose, intracellular (IC) PK in the MAC-infected monocytes were established. EBO PK/PD index parameters including 0-168h area under the concentrations-time curve (AUC0-168), peak concentration, or % of time concentration persists above the intracellular MIC (%TMIC), which was 0.5 mg/L, were modeled versus total MAC burden using the inhibitory sigmoid maximal effect (Emax) model. The PK/PD index was chosen using Akaike Information Criteria (AIC). For AMR, EBO PK/PD index exposure value versus EBO-resistant MAC burden were modeled using a quadratic function, and the best model was chosen using AIC. Results The measured EBO concentrations demonstrated PKs shown in Figure 1. The median EBO IC versus extracellular (IC/EC) elimination rate constants were 0.018h-1 versus 0.061h-1 (p&amp;lt; 0.0001), which means slower IC EBO elimination, leading to IC/EC to AUC ratio of 11. Based on AIC scores in Table 1, the PK/PD driver for microbial kill was unequivocally AUC on each sampling day. For AMR the PK/PD driver was also AUC. Table 1.Corrected Akaike Information Criteria (AIC) Scores for PK/PD Indicesa-The intracellular EBO MIC was 0.5 mg/LFigure 1.Epetraborole concentrations achieved in the HFS-MAC during the 168-hour dosing interval. Epetraborole concentrations were measured for each of the four dosing schedules, and are shown together with compartmental pharmacokinetics modeling during the 168-hour dosing interval. A. Twice a day dosing. B. Once a day dosing. C. Once every 3.5 days. D. Once every 7 days. Conclusion The PK/PD index best associated with EBO microbial kill and AMR was AUC. Disclosures Shruti Athale, PhD, Praedicare Inc.: Stocks/Bonds Moti Chapagain, MD, PhD, Praedicare Inc.: Stocks/Bonds Jotam Pasipanodya, MD, PhD, Praedicare Inc.: Employee MRK Alley, PhD, ABBOTT LABS: Stocks/Bonds|ABBVIE: Stocks/Bonds|AN2 Therapeutics: Author on epetraborole patent|AN2 Therapeutics: Salary|AN2 Therapeutics: Ownership Interest|AVANOS MED INC: Stocks/Bonds|NABRIVA THERAPEUTICS PLC: Stocks/Bonds|NOVARTIS AG: Stocks/Bonds Tawanda Gumbo, MD, Hydronium Biopharma: Ownership Interest|Hydronium Biopharma: Stocks/Bonds|Praedicare Africa Pvt Ltd: Board Member|Praedicare Africa Pvt Ltd: Ownership Interest|Praedicare Africa Pvt Ltd: Stocks/Bonds|Praedicare Inc.: Patents|Praedicare Inc.: Ownership Interest|Praedicare Inc.: Stocks/Bonds.

1697. Dose-response Studies of the Novel Bacterial Leucyl-tRNA Synthetase Inhibitor, Epetraborole, in the Intracellular Hollow Fiber System Model of Mycobacterium avium complex Lung Disease

Abstract Background Based on meta-analyses the current standard-of-care regimen (SOC) for Mycobacterium avium complex (MAC) lung disease achieves a sustained sputum conversion rate of ∼54% at best. Epetraborole (EBO) is a boron-containing oral inhibitor of bacterial leucyl-tRNA synthetase, an essential enzyme in protein synthesis; EBO demonstrates potent activity against nontuberculous mycobacteria. To identify EBO exposure-effect parameters we used the intracellular hollow fiber system model of intracellular pulmonary MAC (HFS-MAC). Methods EBO was administered once daily at 8 different doses to HFS-MAC replicates for 28 days to achieve a half-life (t½) of 10.4h and the 0-24h area under the concentration-time curves (AUC0-24) that cover the observed AUC values in humans. The SOC combination of clarithromycin (CLR), ethambutol (EMB), and rifabutin (RFB) at human intrapulmonary pharmacokinetic (PK) concentrations was used. The central compartment of each HFS-MAC unit was sampled throughout the 28 days to assess PK parameters as was the peripheral compartment for total bacterial burden and the EBO-resistant bacterial burden. EBO AUC versus total MAC burden was modeled using the inhibitory sigmoid maximal effect (Emax) model. EBO AUC versus EBO-resistant MAC burden was modeled using a quadratic function. Results Measured EBO concentrations demonstrated a t1/2 of 10h. For SOC, the AUC for CLR, EMB, and RFB was 60 mg*h/L (t1/2=6h), 39 mg*h/L (t1/2=8h), and 1.5 mg*h/L (t1/2=45h), respectively, similar to human lung concentrations. Changes in MAC burden over 28 days (Fig. 1) show that highest EBO exposures matched SOC until day 14. The exposure versus effect on each sampling day is shown in Fig. 2. The EBO AUC mediating 50% of Emax (EC50) was an AUC of 22 mg*h/L (95% confidence interval [CI]: 16-70), and the EC80 was an AUC of 47.5 mg*h/L (CI: 34.6-151.2). The relationship between AUC and EBO-resistant subpopulation (Fig. 3) shows that an AUC0-24 of 47.5 mg*h/L, the same as the EC80 for microbial kill, was associated with resistance suppression, as was the addition of SOC to EBO. Figure 1.Changes in bacterial burden over the 28-day dosing period. Bacterial burden on serial samples from all HFS-MAC units and replicates over 28days are shown. The highest epetraborole exposures demonstrated the same effectiveness as the three drug SOC until day 14, after which it failed as resistance emerged. On the other hand adding epetraborole at an AUC of 43.6 mg*h/L to the SOC led to much faster kill (i.e, higher kill slopes) than SOC or the epetraborole monotherapy at the same AUC. Figure 2.Epetraborole exposure versus effect on bacterial burden. Shown are inhibitory sigmoid Emax curves for epetraborole AUC versus log10 CFU/mL on each sampling day, as well as various extents of microbial kill such as stasis (holding burden similar to day 0), 1 log CFU/mL kill and 2 log CFU/mL kill. Beyond day 3, epetraborole killed &amp;gt; 1log CFU/mL, which means it was rapidly bactericidal. Figure 3.Epetraborole exposure versus epetraborole-resistant subpopulation. Drug-resistant burden is shown as log10 CFU/mL. The addition of SOC to EBO totally suppressed emergence of any resistance on all days. Conclusion EBO monotherapy with an AUC0-24 &amp;gt; 16.9 mg*h/L killed &amp;gt; 1.0 log10 CFU/mL of MAC compared to day 0. At the EC80, EBO killed at least 2.0 log10 CFU/mL, thus was highly bactericidal. EBO plus SOC demonstrated resistance suppression. Disclosures Moti Chapagain, MD, PhD, Praedicare Inc.: Stocks/Bonds Shruti Athale, PhD, Praedicare Inc.: Stocks/Bonds Jotam Pasipanodya, MD, PhD, Praedicare Inc.: Employee MRK Alley, PhD, ABBOTT LABS: Stocks/Bonds|ABBVIE: Stocks/Bonds|AN2 Therapeutics: Author on epetraborole patent|AN2 Therapeutics: Salary|AN2 Therapeutics: Ownership Interest|AVANOS MED INC: Stocks/Bonds|NABRIVA THERAPEUTICS PLC: Stocks/Bonds|NOVARTIS AG: Stocks/Bonds Tawanda Gumbo, MD, Hydronium Biopharma: Ownership Interest|Hydronium Biopharma: Stocks/Bonds|Praedicare Africa Pvt Ltd: Board Member|Praedicare Africa Pvt Ltd: Ownership Interest|Praedicare Africa Pvt Ltd: Stocks/Bonds|Praedicare Inc.: Patents|Praedicare Inc.: Ownership Interest|Praedicare Inc.: Stocks/Bonds.

Isoniazid pharmacokinetics/pharmacodynamics as monotherapy and in combination regimen in the hollow fiber system model of Mycobacterium kansasii

BackgroundThere is limited high quality evidence to guide the optimal doses of drugs for the treatment of Mycobacterium kansasii pulmonary disease (Mkn-PD). MethodsWe performed (1) minimum inhibitory concentration experiment, (2) isoniazid dose-response study using the hollow fiber system model (HFS-Mkn) to determine PK/PD optimized exposure, and (3) another HFS-Mkn study to determine the efficacy of high dose isoniazid (15 mg/kg/day) with standard dose rifampin (10 mg/kg/day) and ethambutol (15 mg/kg/day). Inhibitory sigmoid maximal effect model and linear regression was used for data analysis. ResultsMIC of the 20 clinical isolates ranged between 0.5 mg/L to 32 mg/L. In the HFS-Mkn, isoniazid monotherapy failed to control the bacterial growth beyond day 7. On day 7, when the maximal Mkn kill was observed, the optimal isoniazid exposure for Mkn kill was calculated as 24hr area under the concentration-time curve to the MIC of 12.41. Target attainment probability of 300 mg/day dose fell below 90% above the MIC of 1 mg/L. High dose isoniazid combination sterilized the HFS-Mkn in 30-days with a kill rate of −0.15 ± 0.02 log10 CFU/mL/day. ConclusionDespite initial kill, isoniazid monotherapy failed due to resistance emergence. Our pre-clinical model derived results suggest that higher than currently recommended 300 mg/day isoniazid dose may achieve better clinical efficacy against Mkn-PD.

Wastewater treatment in large-scale novel corrugated-sheet MBR

This is a threefold study concerning a novel corrugated-sheet MBR. Besides the optimization of the hydrodynamics and of air consumption to achieve excellent amelioration of fouling, this study introduces a novel corrugated sheet (CS) membrane to the research community. The CS membrane has a general plate configuration similar to a standard flat sheet (FS) membrane but at 1.6 mm thickness, it is much thinner. The rows of hemispherical hollow units on each side create corrugations, and coupled with the thinness of the plate they give a surface area per unit volume value around that of hollow fiber systems. The hydrodynamics and fouling of the CS membrane were compared with those of FS membrane through computational fluid dynamics (CFD) simulation and experiments. Based upon these results a large-scale corrugated sheet membrane bioreactor (CS-MBR) with four decks was designed. The study included a consideration of three different designs of aerators, the spacing between the decks and the aeration rate. With the recommended partitioning design of aerator, the optimized nozzle velocity was found to be 13 m/s corresponding to a world-leading specific aeration demand, SADm (aeration amount per unit membrane area per unit time), of 0.074 Nm3m−2 h−1. This corresponds to a 70 % reduction with respect to a FSMBR operated with slug bubbling and is just one-eighth of the traditional industrial usage of 0.3 to 0.58 Nm3m−2 h−1 depending on format of the system.