We hypothesize that low-level efflux pump expression is the first step in development of high-level drug resistance mycobacteria. performed 28-day azithromycin dose-effect and dose-scheduling studies our hollow-fiber model disseminated Mycobacterium avium-M. intracellulare complex. Both microbial kill emergence were most closely linked to within-macrophage area under concentration-time curve (AUC)/MIC ratio. Quantitative PCR revealed subtherapeutic exposures over 3 days led a 56-fold...

Background. The role of drug concentrations in clinical outcomes children with tuberculosis is unclear. Target for dose optimization are unknown. Methods. Plasma measured Indian were modeled using compartmental pharmacokinetic analyses. followed until end therapy to ascertain failure or death. An ensemble artificial intelligence algorithms, including random forests, was used identify predictors outcome from among 30 clinical, laboratory, and variables. Results. Among the 143 known outcomes,...

ABSTRACT Linezolid has an excellent sterilizing effect in tuberculosis patients but high adverse event rates. The dose that would maximize efficacy and minimize toxicity is unknown. We performed linezolid dose-effect dose-scheduling studies the hollow fiber system model of (HFS-TB) for effect. HFS-TB units were treated with several doses to mimic human-like intrapulmonary pharmacokinetics repetitively sampled drug concentration, total bacterial burden, linezolid-resistant subpopulations, RNA...

Levofloxacin is used for the treatment of multidrug-resistant tuberculosis; however optimal dose unknown.We hollow fiber system model tuberculosis (HFS-TB) to identify 0-24 hour area under concentration-time curve (AUC0-24) minimum inhibitory concentration (MIC) ratios associated with maximal microbial kill and suppression acquired drug resistance (ADR) Mycobacterium (Mtb). Levofloxacin-resistant isolates underwent whole-genome sequencing. Ten thousands patient Monte Carlo experiments (MCEs)...

Ceftazidime-avibactam is highly efficacious against extensive- and multidrug-resistant strains of Mycobacterium tuberculosis .

ABSTRACT Mycobacterium abscessus causes chronic pulmonary infections that are extremely difficult to cure. The currently recommended combination therapy is associated with high failure rates and relapse. Tigecycline has been explored in salvage regimens, a response rate of 43% those who received at least month therapy. We performed dose-response study hollow-fiber system model M. infection which we recapitulated tigecycline human concentration-time profiles 8 different doses for 21 days....

In a hollow-fiber model, we mimicked the drug exposures achieved in lungs of humans treated with standard amikacin, clarithromycin, and cefoxitin combination therapy for Mycobacterium abscessus infection. At optimal dosing, kill rate -0.09 (95% confidence interval, -0.04 to 0.03) log10 CFU per ml/day was over first 14 days, after which there regrowth due acquired resistance. Thus, regimen quickly failed. A new is needed.

Ethambutol, together with a macrolide, is the backbone for treatment of disseminated Mycobacterium avium disease. However, at standard dose 15 mg/kg body weight/day, ethambutol efficacy limited. In addition, susceptibility breakpoints have consistently failed to predict clinical outcome. We performed dose-effect studies extracellular M. as well bacilli within human macrophages. The maximal kill rate (E(max)) against was 5.54 log(10) CFU/ml, compared 0.67 CFU/ml intracellular avium, after 7...

The treatment of pulmonary Mycobacterium abscessus disease is associated with very high failure rates and easily acquired drug resistance. Amikacin the key in regimens, but optimal doses are unknown. No good preclinical model exists to perform formal pharmacokinetics/pharmacodynamics experiments determine these doses. We developed a hollow-fiber system M. studied amikacin exposure effects dose scheduling. mimicked human pharmacokinetics. Both microbial kill resistance were linked peak...

Treatment of disseminated tuberculosis in children ≤ 6 years has not been optimized. The pyrazinamide-containing combination regimen used to treat babies and toddlers was extrapolated from adult pulmonary tuberculosis. Due hepatotoxicity worries, there are no dose–response studies children. We designed a hollow fiber system model intracellular with co-perfused three-dimensional organotypic liver modules simultaneously test for efficacy toxicity. utilized pediatric pharmacokinetics...

Background. The regimen of linezolid and moxifloxacin was found to be efficacious in the hollow fiber system model pediatric intracellular tuberculosis. However, its kill rate slower than standard 3-drug isoniazid, rifampin, pyrazinamide. We wanted examine effect adding a third oral agent, faropenem, this dual combination. Methods. performed series studies Mycobacterium tuberculosis, by mimicking pharmacokinetics each antibiotic. First, we varied percentage time that faropenem persisted...

No treatment regimens have been specifically designed for children, in whom tuberculosis is predominantly intracellular. Given their activity as monotherapy and ability to penetrate many diseased anatomic sites that characterize disseminated tuberculosis, linezolid moxifloxacin could be combined form a regimen this need. We examined microbial kill of intracellular Mycobacterium (Mtb) by the combination multiple exposures 7-by-7 mathematical matrix. then used hollow fiber system (HFS) model...

Infants and toddlers often present with disseminated lymph node tuberculosis, in which Mycobacterium tuberculosis (Mtb) is predominantly intracellular. Linezolid, used to treat adults, has not been formally studied infants. clear linezolid 5 times faster than adults achieve lower 0- 24-hour area under the concentration-time curves (AUC0-24). To mimic intracellular disease, we infected human-derived THP-1 macrophages Mtb inoculated hollow fiber systems. We performed dose-effect...

Organisms of the Mycobacterium avium-intracellulare complex (MAC) have been demonstrated to be susceptible moxifloxacin. However, clinical data on how utilize moxifloxacin treat disseminated MAC are scanty. In addition, there no pharmacokinetic-pharmacodynamic (PK/PD) studies performed for infection. We utilized an in vitro PK/PD model intracellular study disease. Moxifloxacin doses, based a serum half-life 12 h, were administered, and 0- 24-h area under concentration-time curve (AUC(0-24))...

To determine if ceftaroline and ceftazidime combined with avibactam are efficacious against pulmonary Mycobacterium avium complex (MAC) disease.First, we performed a concentration-effect study of ceftaroline/avibactam extracellular MAC in test tubes. Given the difficulty obtaining at time experimentation, used single concentration commercial ceftazidime/avibactam, two sets non-treated controls, one ceftazidime/avibactam other without. After finding antimicrobial activity 'control',...

To determine if tedizolid is effective for pulmonary Mycobacterium avium complex (MAC) disease, and to use pharmacokinetics/pharmacodynamics design optimal doses. We performed an exposure–response experiment in the hollow-fibre system model of intracellular MAC (HFS-MAC). mimicked concentration–time profiles achieved lungs patients treated once daily 28 days. The HFS-MAC was sampled at intervals pharmacokinetics burden. identified 0–24 h area under curves MIC (AUC0–24/MIC) ratios associated...

ABSTRACT The modern chemotherapy era started with Fleming's discovery of benzylpenicillin. He demonstrated that benzylpenicillin did not kill Mycobacterium tuberculosis . In this study, we found >64 mg/liter static concentrations killed 1.16 to 1.43 log 10 CFU/ml below starting inoculum extracellular and intracellular M. over 7 days. When added the β-lactamase inhibitor avibactam, maximal ( E max ) log-phase-growth was 6.80 ± 0.45 at a 50% effective concentration (EC 50 15.11 2.31...

Aminoglycosides such as amikacin are currently used for the treatment of multidrug-resistant tuberculosis (MDR-TB). However, formal pharmacokinetic/pharmacodynamic (PK/PD) studies to identify exposures and dosing schedules that optimize Mycobacterium killing have not been performed. It is believed aminoglycosides do work well under acidic conditions, which, if true, would mean poor sterilizing activity against semidormant bacilli at low pH. We performed time-kill compare bactericidal effect...

When treated with the same antibiotic dose, children achieve different 0- to 24-hour area under concentration-time curves (AUC0-24) because of maturation and between-child physiological variability on drug clearance. Children are also infected by Mycobacterium tuberculosis isolates minimum inhibitory concentrations (MICs). Thus, each child will AUC0-24/MIC ratios when dose. We used 10 000-subject Monte Carlo experiments identify oral doses linezolid, moxifloxacin, faropenem that would...

Ethionamide is used to treat multidrug-resistant tuberculosis (MDR-TB). The antimicrobial pharmacokinetics/pharmacodynamics, the contribution of ethionamide multidrug regimen, and events that lead acquired drug resistance (ADR) are unclear.We performed a multidose hollow fiber system model (HFS-TB) study identify 0-24 hour area under concentration-time curve (AUC0-24) minimum inhibitory concentration (MIC) ratios achieved maximal kill ADR suppression, defined as target exposures....

Linezolid exhibits remarkable sterilizing effect in tuberculosis; however, a large proportion of patients develop serious adverse events. The congener tedizolid could have better side-effect profile, but its potential is unknown.We performed 42-day exposure-effect and dose-fractionation study the hollow fiber system model tuberculosis for effect, using human-like intrapulmonary pharmacokinetics. Bacterial burden was examined time to positivity (TTP) colony-forming units (CFUs)....

Mycobacterium aviumcomplex is now the leading mycobacterial cause of chronic pneumonia in United States. Macrolides and ethambutol form backbone regimen used treatment pulmonary disease. However, therapy outcomes remain poor, with microbial cure rates 4% cavitary The dose azithromycin has mostly been borrowed from that to treat other bacterial pneumonias; there are no formal dose-response studies pulmonaryM. aviumdisease optimal unclear. We utilized population pharmacokinetics...