Sulbactam-Durlobactam Plus Ceftriaxone Dosing and Novel Treatment Regimens for Lung Disease.

Background: IDSA guideline-based therapy achieves sputum culture conversion rates in 20-34% of patients with (MAB) lung disease (LD). Double-β-lactam combinations have been proposed to improve cure, based on time-kill curves.

Methods: We performed minimum inhibitory concentrations (MICs) experiments followed by hollow fiber system model of MAB-LD (HFS-MAB) exposure-effect studies with sulbactam-durlobactam administered every 8h (q8h), q12h, and q24h, to identify target exposures.

Tigecycline pharmacodynamics in the hollow fiber system of -complex lung disease, and the utility of MICs and time-kill studies in drug development.

Background: Guideline-based therapy (GBT) drugs for (MAC) lung disease (LD) were chosen in part because they have low MICs. Despite these low MICs, GBT achieves six-month sustained sputum culture conversion in only 43% of patients.

Methods: First, we co-incubated tigecycline with MAC for seven days in time-kill studies and calculated the exposure mediating 50% of maximal effect (E) or EC.

Ivacaftor affects the susceptibility of standard-of-care drugs used to treat lung disease.

Patients with cystic fibrosis have dysfunctional cystic fibrosis transmembrane conductance regulator (CFTR), and this predisposes them to nontuberculous mycobacteria (NTM), including (MAB) infection. We found that one of the CFTR modulators, ivacaftor, kills MAB in a concentration-dependent manner, with killing efficacy comparable to amikacin and imipenem, drugs in guideline-based regimens. Using clinical isolates of MAB, amikacin 1/4× MIC concentration combined with ivacaftor killed 2.

A mechanistic understanding of the effect of VraS histidine kinase single-point mutation on antibiotic resistance.

Bacterial genomic mutations in have been detected in isolated resistant clinical strains, yet their mechanistic effect on the development of antimicrobial resistance remains unclear. Resistance-associated regulatory systems acquire adaptive mutations under stress conditions that may lead to a gain-of-function effect and contribute to the resistance phenotype. Here, we investigate the effect of a single-point mutation (T331I) in VraS histidine kinase, part of the VraSR two-component system in .

Repurposing drugs to advance the treatment of Buruli ulcer.

Aligned with the World Health Organization's Road Map, there is an unmet need for research to improve the treatment of Buruli ulcer caused by . The repurposing of drugs could speed up new regimen development to treat Buruli ulcer. Using a virulent reporter strain of with intrinsic bioluminescence (MuAL), we compared the minimum inhibitory concentration (MIC) of moxifloxacin, bedaquiline, telacebec, tebipenem, omadacycline, and epetraborole with standard-of-care drugs-rifampin and clarithromycin.

A mechanistic understanding of the effect of VraS histidine kinase single point mutation on antibiotic resistance.

Unlabelled: Bacterial genomic mutations in have been detected in isolated resistant clinical strains, yet their mechanistic effect on the development of antimicrobial resistance remains unclear. The resistance-associated regulatory systems acquire adaptive mutations under stress conditions that may lead to a gain of function effect and contribute to the resistance phenotype. Here, we investigate the effect of a single-point mutation (T331I) in VraS histidine kinase, part of the VraSR two-component system in VraSR senses and responds to environmental stress signals by upregulating gene expression for cell wall synthesis.

Fluoroquinolones and rifampin combination in the backdrop of heteroresistant tuberculosis.

The impact of heteroresistance on tuberculosis (TB) treatment outcomes is unclear, as is the role of different rifampin and isoniazid exposures on developing resistance mutations. Hollow fiber system model of TB (HFS-TB) units were inoculated with drug-susceptible () and treated with isoniazid and rifampin exposure identified in a clinical trial as leading to treatment failure and acquired drug resistance. Systems were sampled for drug concentration measurements, estimation of total and drug-resistant , and small molecule overlapping reads (SMOR) analysis for the detection of heteroresistance.

Imipenem Pharmacokinetics/Pharmacodynamics in Preclinical Hollow Fiber Model, Dose Finding in Virtual Patients, and Clinical Evidence of Efficacy for Mycobacterium abscessus Lung Disease.

Background: Guideline-based therapy (GBT) for Mycobacterium abscessus (Mab) lung disease achieves sputum culture conversion (SCC) rates of 35%. This poor GBT efficacy is mirrored in the hollow fiber system model of Mab (HFS-Mab). While imipenem is part of GBT, its biologic effect, with or without β-lactamase inhibitors, is unproven.

Omadacycline drug susceptibility testing for non-tuberculous mycobacteria using oxyrase to overcome challenges with drug degradation.

Background: Drug susceptibility testing (DST) protocol of omadacycline against non-tuberculous mycobacteria has not yet been established. We developed a method to accurately determine MIC omadacycline MIC against Mycobacterium abscessus (Mab), Mycobacterium avium-complex (MAC), and Mycobacterium kansasii (Mkn).

Methods: First, we identified the oxyrase concentration not affecting Mab, MAC, and Mkn growth followed by omadacycline MIC experiments with and without oxyrase using reference and clinical strains.

Omadacycline pharmacokinetics/pharmacodynamics and efficacy against multidrug-resistant 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). () 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.

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

Background: 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).

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

Background: 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).

Objective: To determine the pharmacokinetics/pharmacodynamics (PK/PD)-optimized exposure of sarecycline and its potential role in treating MAC-PD.

Methods: We performed MIC studies with MAC ATCC 700898 and 19 clinical isolates and test-tube static concentration-response studies.

Meropenem-vaborbactam restoration of first-line drug efficacy and comparison of meropenem-vaborbactam-moxifloxacin versus BPaL MDR-TB regimen.

Background: Meropenem in combination with β-lactamase inhibitors (BLIs) and other drugs was tested to identify alternative treatment regimens for multidrug-resistant tuberculosis (MDR-TB).

Methods: The following were performed: (1) MIC experiments; (2) static time-kill studies (STKs) with different BLIs; and (3) a hollow fibre model system of TB (HFS-TB) studies with meropenem-vaborbactam combined with human equivalent daily doses of 20 mg/kg or 35 mg/kg rifampin, or moxifloxacin 400 mg, or linezolid 600 mg vs. bedaquiline-pretonamid-linezolid (BPaL) for MDR-TB.

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

Background: Guideline-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 log 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.

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

Background: 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.

Methods: 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).

Pharmacokinetics and pharmacodynamics of anti-tuberculosis drugs: An evaluation of , methodologies and human studies.

There has been an increased interest in pharmacokinetics and pharmacodynamics (PKPD) of anti-tuberculosis drugs. A better understanding of the relationship between drug exposure, antimicrobial kill and acquired drug resistance is essential not only to optimize current treatment regimens but also to design appropriately dosed regimens with new anti-tuberculosis drugs. Although the interest in PKPD has resulted in an increased number of studies, the actual bench-to-bedside translation is somewhat limited.

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

Background: There is limited high quality evidence to guide the optimal doses of drugs for the treatment of Mycobacterium kansasii pulmonary disease (Mkn-PD).

Methods: We 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.

Minocycline intra-bacterial pharmacokinetic hysteresis as a basis for pharmacologic memory and a backbone for once-a-week pan-tuberculosis therapy.

There is need for shorter duration regimens for the treatment of , that can treat patients regardless of multidrug resistance status (pan-tuberculosis). We combined minocycline with tedizolid, moxifloxacin, and rifampin, in the hollow fiber system model of and mimicked each drugs' intrapulmonary pharmacokinetics for 28 days. Minocycline-tedizolid was administered either as a once-a-week or a daily regimen.

Challenges and a potential solution to perform drug susceptibility testing of omadacycline against nontuberculous mycobacteria.

Background: Minimum inhibitory concentration (MIC) of slow growing mycobacteria (SGM) often do not correlate with the treatment response. Among the challenges is the identification of MIC of drugs that degrade in solution faster than the doubling time of the SGM.

Methods: First, we identified the rate of omadacycline degradation in solution, and its effect on the rapidly growing methicillin resistant Staphylococcus aureus (MRSA).