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 rates (SCC) of 35%. This poor GBT efficacy is mirrored in the hollow fiber system model of Mab (HFS-Mab). While imipenem is part of GBT, biological 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.

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.

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).

Omadacycline Pharmacokinetics/Pharmacodynamics in the Hollow Fiber System Model and Potential Combination Regimen for Short Course Treatment of Mycobacterium kansasii Pulmonary Disease.

The 12-month therapy duration for the treatment of Mycobacterium kansasii pulmonary disease calls for more efficacious drugs for better treatment outcomes and to shorten the therapy duration. We performed (i) omadacycline MIC with M. kansasii ATCC 12478 strain and 21 clinical isolates, (ii) dose-response study in the hollow fiber system model of M.

Rifampin Pharmacokinetics/Pharmacodynamics in the Hollow-Fiber Model of Mycobacterium kansasii Infection.

There is limited high-quality evidence to guide the optimal treatment of Mycobacterium kansasii pulmonary disease. We retrospectively collected clinical data from 33 patients with M. kansasii pulmonary disease to determine the time-to-sputum culture conversion (SCC) upon treatment with a standard combination regimen consist of isoniazid-rifampin-ethambutol.

Tick Intrastadial Feeding and Its Role on IgE Production in the Murine Model of Alpha-gal Syndrome: The Tick "Transmission" Hypothesis.

Recent studies have provided strong evidence indicating that lone star tick bites are a cause of AGS (alpha-gal syndrome, also known as red meat allergy RMA) in humans. AGS is characterized by an increase in IgE antibody production against galactose-alpha-1,3-galactose (aGal), which is a common glycan found in mammalian tissue, except in Old World monkeys and humans. The main causative factor of AGS, the lone star tick (), is broadly distributed throughout the east and midwest of the United States and is a vector of a wide range of human and animal pathogens.

An overview of drugs for the treatment of Mycobacterium kansasii pulmonary disease.

Objectives: The aim of this study was to determine and compare the efficacy of drugs to treat Mycobacterium kansasii (Mkn) pulmonary disease by performing minimum inhibitory concentration (MIC) determination and time-kill studies.

Methods: We determined the MICs to 13 drugs against the Mkn standard laboratory strain ATCC 12478 and 20 clinical isolates and performed time-kill studies with 18 drugs from different classes using the standard laboratory strain of Mkn. The β-lactam antibiotics were tested with or without the combination of the β-lactamase inhibitor avibactam.

Unexpected winter questing activity of ticks in the Central Midwestern United States.

Unexpected questing activity of ticks was noted during the winter months of January and February in the Central Midwestern states of Kansas, Missouri, Oklahoma, and Arkansas. From nine geographically distinct locations, four species of ticks were collected using the flagging method, of which the lone star tick, Amblyomma americanum, was most abundant, followed by the American dog tick, Dermacentor variabilis, the Gulf coast tick, Amblyomma maculatum, and the Black legged tick, Ixodes scapularis. More A.

Comparison of Rifamycins for Efficacy Against Complex and Resistance Emergence in the Hollow Fiber Model System.

Rifamycins are integral part of the combination regimen for treatment of pulmonary [MAC] infection, but different practitioners prefer different rifamycins. The objective of the study was to compare microbial kill and resistance emergence of rifamycins using principles of pharmacokinetics/pharmacodynamics. First, we identified rifamycin MICs in 20 MAC isolates from patients followed by concentration-response studies in test-tubes.

Diversity and seasonality of host-seeking ticks in a periurban environment in the Central Midwest (USA).

Between March 2014 and February 2017, host-seeking ticks were collected during the late spring and summer months seasonally, and as well as continually through all seasons from several sites in a periurban environment in Pittsburg, Kansas, located in the Central Midwestern United States. All three post-emergent life-stages of Amblyomma americanum, and the adults of three other ticks viz. Dermacentor variabilis, A.

Assessing the current and future potential geographic distribution of the American dog tick, Dermacentor variabilis (Say) (Acari: Ixodidae) in North America.

The American dog tick, Dermacentor variabilis, is a veterinary- and medically- significant tick species that is known to transmit several diseases to animal and human hosts. The spatial distribution of this species in North America is not well understood, however; and knowledge of likely changes to its future geographic distribution owing to ongoing climate change is needed for proper public health planning and messaging. Two recent studies have evaluated these topics for D.

Alpha-Gal and Cross-Reactive Carbohydrate Determinants in the N-Glycans of Salivary Glands in the Lone Star Tick, .

Ticks are important ectoparasites and vectors of numerous human and animal pathogens. Ticks secrete saliva that contains various bioactive materials to evade the host defense system, and often facilitates the pathogen transmission. In addition, the Lone star tick saliva is thought to be the sensitizer in red meat allergy that is characterized by an allergic reaction to glycan moieties carrying terminal galactose-alpha-1,3-galactose (aGal).

Antigen-Specific CD4CD8 Double-Positive T Cells Are Increased in the Blood and Spleen During Infection in the Canine Host.

is an obligate intracellular bacterium belonging to the order, Rickettsiales and is a frequent cause of severe and fatal tick-borne infection in people in North America. The reservoir host for is the white-tailed deer, while humans and dogs are regarded as common incidental hosts. In dogs, we and others have shown that establishes a chronic infection that persists for several weeks to months, while promoting the development of Th1 and Th17 cellular responses and pathogen-specific humoral immunity.