scholarly journals Higher Dosing of Rifamycins Does Not Increase Activity against Mycobacterium tuberculosis in the Hollow-Fiber Infection Model

2021 ◽  
Vol 65 (4) ◽  
Author(s):  
E. D. Pieterman ◽  
S. van den Berg ◽  
A. van der Meijden ◽  
E. M. Svensson ◽  
H. I. Bax ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Drug Development ◽  
Hollow Fiber ◽  
Standard Dose ◽  
Free Fraction ◽  
Infection Model ◽  
Preclinical Model ◽  
Content Type ◽  
Development Pipeline

ABSTRACT Improvements in the translational value of preclinical models can allow more-successful and more-focused research on shortening the duration of tuberculosis treatment. Although the hollow-fiber infection model (HFIM) is considered a valuable addition to the drug development pipeline, its exact role has not been fully determined yet. Since the strategy of increasing the dose of rifamycins is being evaluated for its treatment-shortening potential, additional in vitro modeling is important. Therefore, we assessed increased dosing of rifampin and rifapentine in our HFIM in order to gain more insight into the place of the HFIM in the drug development pipeline. Total and free-fraction concentrations corresponding to daily dosing of 2.7, 10, and 50 mg of rifampin/kg of body weight, as well as 600 mg and 1,500 mg rifapentine, were assessed in our HFIM using the Mycobacterium tuberculosis H37Rv strain. Drug activity and the emergence of drug resistance were assessed by CFU counting and subsequent mathematical modeling over 14 days, and pharmacokinetic exposures were checked. We found that increasing rifampin exposure above what is expected with the standard dose did not result in higher antimycobacterial activity. For rifapentine, only the highest concentration showed increased activity, but the clinical relevance of this observation is questionable. Moreover, for both drugs, the emergence of resistance was unrelated to exposure. In conclusion, in the simplest experimental setup, the results of the HFIM did not fully correspond to preexisting clinical data. The inclusion of additional parameters and readouts in this preclinical model could be of interest for proper assessment of the translational value of the HFIM.

scholarly journals Advanced Quantification Methods To Improve the 18b Dormancy Model for Assessing the Activity of Tuberculosis Drugs In Vitro

2020 ◽  
Vol 64 (7) ◽  
Author(s):  
E. D. Pieterman ◽  
M. J. Sarink ◽  
C. Sala ◽  
S. T. Cole ◽  
J. E. M. de Steenwinkel ◽  
...  
Keyword(s):  
Drug Development ◽  
Area Under The Curve ◽  
High Dose ◽  
Current Form ◽  
Content Type ◽  
Solid Media ◽  
Development Pipeline ◽  
The Difference ◽  
Time Kill

ABSTRACT One of the reasons for the lengthy tuberculosis (TB) treatment is the difficulty to treat the nonmultiplying mycobacterial subpopulation. In order to assess the ability of (new) TB drugs to target this subpopulation, we need to incorporate dormancy models in our preclinical drug development pipeline. In most available dormancy models, it takes a long time to create a dormant state, and it is difficult to identify and quantify this nonmultiplying condition. The Mycobacterium tuberculosis 18b strain might overcome some of these problems, because it is dependent on streptomycin for growth and becomes nonmultiplying after 10 days of streptomycin starvation but still can be cultured on streptomycin-supplemented culture plates. We developed our 18b dormancy time-kill kinetics model to assess the difference in the activity of isoniazid, rifampin, moxifloxacin, and bedaquiline against log-phase growth compared to the nonmultiplying M. tuberculosis subpopulation by CFU counting, including a novel area under the curve (AUC)-based approach as well as time-to-positivity (TTP) measurements. We observed that isoniazid and moxifloxacin were relatively more potent against replicating bacteria, while rifampin and high-dose bedaquiline were equally effective against both subpopulations. Moreover, the TTP data suggest that including a liquid culture-based method could be of additional value, as it identifies a specific mycobacterial subpopulation that is nonculturable on solid media. In conclusion, the results of our study underline that the time-kill kinetics 18b dormancy model in its current form is a useful tool to assess TB drug potency and thus has its place in the TB drug development pipeline.

scholarly journals Pharmacokinetics/Pharmacodynamics of Vaborbactam, a Novel Beta-Lactamase Inhibitor, in Combination with Meropenem

2018 ◽  
Vol 63 (1) ◽  
Author(s):  
David C. Griffith ◽  
Mojgan Sabet ◽  
Ziad Tarazi ◽  
Olga Lomovskaya ◽  
Michael N. Dudley
Keyword(s):  
Hollow Fiber ◽  
Infection Model ◽  
Beta Lactamase ◽  
Fiber Model ◽  
Content Type ◽  
Development Of Resistance ◽  
Wide Range ◽  
Tract Infections ◽  
Lactamase Inhibitor

ABSTRACT Vaborbactam is a novel beta-lactamase inhibitor with activity against important beta-lactamases, in particular, serine carbapenemases, and is currently approved in combination with meropenem as Vabomere for the treatment of complicated urinary tract infections, including pyelonephritis. This combination is highly active against Gram-negative pathogens, especially Klebsiella pneumoniae carbapenemase (KPC)-producing carbapenem-resistant Enterobacteriaceae. The objective of these studies was to evaluate vaborbactam pharmacokinetics (PK) and pharmacodynamics (PD) relationships for efficacy in a neutropenic mouse thigh infection model, as well as in an in vitro hollow-fiber infection model, in combination with a fixed exposure of meropenem using KPC-containing strains of Enterobacteriaceae. For both models, the meropenem dosage regimen was designed to simulate a 2-g dose administered every eight hours (q8h) by 3-h infusion. Vaborbactam dosage regimens were designed to produce a wide range of 24-h areas under the concentration-time curves (AUCs) in the thigh infection model. However, for the hollow-fiber model, the AUCs were limited to values of 192, 320, or 550 mg · h/liter. In both the animal and in vitro models, the PK-PD parameter that best described the antibacterial activity of vaborbactam, when administered in combination with meropenem at exposures equivalent to 2 g dosed q8h by 3-h infusion in humans, was the 24-h free vaborbactam AUC/meropenem-vaborbactam (with vaborbactam at 8 mg/liter) MIC ratio. The magnitude of this ratio for bacteriostasis was 9 to 12 and the magnitude to observe a 1-log kill was 18 to 38. In addition, a magnitude greater than 24 suppressed the development of resistance in the in vitro hollow-fiber model.

scholarly journals Effect of Coadministration of Moxifloxacin and Rifampin on Mycobacterium tuberculosis in a Murine Aerosol Infection Model

2012 ◽  
Vol 56 (6) ◽  
pp. 3054-3057 ◽  
Author(s):  
V. Balasubramanian ◽  
S. Solapure ◽  
S. Gaonkar ◽  
K. N. Mahesh Kumar ◽  
R. K. Shandil ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Hollow Fiber ◽  
Lung Model ◽  
Control Group ◽  
Infection Model ◽  
Content Type ◽  
Days Of Therapy ◽  
Cell Kill ◽  
Aerosol Infection

ABSTRACTCoadministration of moxifloxacin and rifampin was evaluated in a murine model ofMycobacterium tuberculosispulmonary infection to determine whether the finding of antagonism documented in a hollow-fiber infection model could be recapitulatedin vivo. Colony counts were followed in a no-treatment control group, groups administered moxifloxacin or rifampin monotherapy, and a group administered a combination of the two agents. Following 18 days of once-daily oral administration to mice infected withM. tuberculosis, there was a reduction in the plasma exposure to rifampin that decreased further when rifampin was coadministered with moxifloxacin. Pharmacodynamic analysis demonstrated a mild antagonistic interaction between moxifloxacin and rifampin with respect to cell kill in the mouse model for tuberculosis (TB). No emergence of resistance was noted over 28 days of therapy, even with monotherapy. This was true even though one of the agents in the combination (moxifloxacin) induces error-prone replication. The previously noted antagonism with respect to cell kill shown in the hollow-fiber infection model was recapitulated in the murine TB lung model, although to a lesser extent.

scholarly journals Determination of the Dynamically Linked Indices of Fosfomycin for Pseudomonas aeruginosa in the Hollow Fiber Infection Model

2018 ◽  
Vol 62 (6) ◽  
Author(s):  
Arnold Louie ◽  
Michael Maynard ◽  
Brandon Duncanson ◽  
Jocelyn Nole ◽  
Michael Vicchiarelli ◽  
...  
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Hollow Fiber ◽  
The United States ◽  
Infection Model ◽  
Combination Regimen ◽  
Bacterial Cells ◽  
Time Curve ◽  
Minimum Concentration ◽  
Content Type

ABSTRACT Fosfomycin is the only expoxide antimicrobial and is currently under development in the United States as an intravenously administered product. We were interested in identifying the exposure indices most closely linked to its ability to kill bacterial cells and to suppress amplification of less susceptible subpopulations. We employed the hollow fiber infection model for this investigation and studied wild-type strain Pseudomonas aeruginosa PAO1. Because of anticipated rapid resistance emergence, we shortened the study duration to 24 h but sampled the system more intensively. Doses of 12 and 18 g/day and schedules of daily administration, administration every 8 h, and administration by continuous infusion for each daily dose were studied. We measured fosfomycin concentrations (by liquid chromatography-tandem mass spectrometry), the total bacterial burden, and the burden of less susceptible isolates. We applied a mathematical model to all the data simultaneously. There was a rapid emergence of resistance with all doses and schedules. Prior to resistance emergence, an initial kill of 2 to 3 log 10 (CFU/ml) was observed. The model demonstrated that the area under the concentration-time curve/MIC ratio was linked to total bacterial kill, while the time that the concentration remained above the MIC (or, equivalently, the minimum concentration/MIC ratio) was linked to resistance suppression. These findings were also seen in other investigations with Enterobacteriaceae ( in vitro systems) and P. aeruginosa (murine system). We conclude that for serious infections with high bacterial burdens, fosfomycin may be of value as a new therapeutic and may be optimized by administering the agent as a continuous or prolonged infusion or by use of a short dosing interval. For indications such as ventilator-associated bacterial pneumonia, it may be prudent to administer fosfomycin as part of a combination regimen.

scholarly journals Evaluation of Once-Daily Vancomycin against Methicillin-Resistant Staphylococcus aureus in a Hollow-Fiber Infection Model

2011 ◽  
Vol 56 (2) ◽  
pp. 682-686 ◽  
Author(s):  
Anthony M. Nicasio ◽  
Jürgen B. Bulitta ◽  
Thomas P. Lodise ◽  
Rebecca E. D'Hondt ◽  
Robert Kulawy ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Hollow Fiber ◽  
Daily Administration ◽  
Dose Fractionation ◽  
Infection Model ◽  
Time Curve ◽  
Once Daily ◽  
Methicillin Resistant ◽  
Content Type

ABSTRACTFor methicillin-resistantStaphylococcus aureus(MRSA) infections, data suggest that the clinical response is significantly better if the total vancomycin area under the concentration-time curve (AUC)/MIC ratio is ≥400. While the AUC/MIC ratio is the accepted pharmacokinetic/pharmacodynamic (PK/PD) index for vancomycin, this target has been achieved using multiple daily doses. We are unaware of a systematically designed dose fractionation study to compare the bactericidal activity of once-daily administration to that of traditional twice-daily administration. A dose fractionation study was performed with vancomycin in anin vitrohollow-fiber infection model against an MRSA USA300 strain (MIC of 0.75 μg/ml) using an inoculum of ∼106CFU/ml. The three vancomycin regimens evaluated for 168 h were 2 g every 24 h (q24h) as a 1-h infusion, 1 g q12h as a 1-h infusion, and 2 g q24h as a continuous infusion. Free steady-state concentrations (assuming 45% binding) for a total daily AUC/MIC ratio of ≥400 were simulated for all regimens. A validated liquid chromatography-tandem mass spectrometry method was used to determine vancomycin concentrations. Although once-daily and twice-daily dosage regimens exhibited total trough concentrations of <15 μg/ml, all regimens achieved similar bactericidal activities between 24 and 168 h and suppressed the amplification of nonsusceptible subpopulations. No colonies were found on agar plates with 3× MIC for any of the treatment arms. Overall, the results suggest that once-daily vancomycin administration is feasible from a PK/PD perspective and merits further inquiry in the clinical arena.

scholarly journals Activity of Moxifloxacin against Mycobacterium tuberculosis in Acid Phase and Nonreplicative-Persister Phenotype Phase in a Hollow-Fiber Infection Model

2018 ◽  
Vol 62 (12) ◽  
Author(s):  
Arnold Louie ◽  
Brandon Duncanson ◽  
Jenny Myrick ◽  
Michael Maynard ◽  
Jocelyn Nole ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Hollow Fiber ◽  
Patient Adherence ◽  
Initial Therapy ◽  
Infection Model ◽  
Early Therapy ◽  
Content Type ◽  
Multiple Exposures ◽  
Metabolic States ◽  
Initiation Of Therapy

ABSTRACT A major goal for improving tuberculosis therapy is to identify drug regimens with improved efficacy and shorter treatment durations. Shorter therapies improve patient adherence to the antibiotic regimens, which, in turn, decreases resistance emergence. Mycobacterium tuberculosis exists in multiple metabolic states. At the initiation of therapy, the bulk of the population is in log-phase growth. Consequently, it is logical to focus initial therapy on those organisms. Moxifloxacin has good early bactericidal activity against log-phase bacteria and is a logical component of initial therapy. It would be optimal if this agent also possessed activity against acid-phase and nonreplicative-persister (NRP) phenotype organisms. In our hollow-fiber infection model, we studied multiple exposures to moxifloxacin (equivalent to 200 mg to 800 mg daily) against strain H37Rv in the acid phase and against strain 18b in streptomycin starvation, which is a model for NRP-phase organisms. Moxifloxacin possesses good activity against acid-phase organisms, generating cell killing of 3.75 log10(CFU/ml) (200 mg daily) to 5.16 log10(CFU/ml) (800 mg daily) over the 28 days of the experiment. Moxifloxacin also has activity against streptomycin-starved strain 18b. The 400- to 800-mg daily regimens achieved extinction at day 28, while the no-treatment control still had 1.96 log10(CFU/ml) culturable. The lowest dose (200 mg daily) still had 0.7 log10(CFU/ml) measurable at day 28, a net kill of 1.26 log10(CFU/ml). Moxifloxacin is an attractive agent for early therapy, because it possesses activity against three metabolic states of M. tuberculosis.

scholarly journals Evaluation of Meropenem Regimens Suppressing Emergence of Resistance in Acinetobacter baumannii with Human Simulated Exposure in anIn VitroIntravenous-Infusion Hollow-Fiber Infection Model

2014 ◽  
Vol 58 (11) ◽  
pp. 6773-6781 ◽  
Author(s):  
Xin Li ◽  
Lin Wang ◽  
Xian-Jia Zhang ◽  
Yang Yang ◽  
Wei-Tao Gong ◽  
...  
Keyword(s):  
Acinetobacter Baumannii ◽  
Hollow Fiber ◽  
Dosage Interval ◽  
Infection Model ◽  
Bacterial Killing ◽  
Content Type ◽  
Dosage Regimens ◽  
Drug Concentrations ◽  
Emergence Of Resistance

ABSTRACTThe emergence of resistance to carbapenems inPseudomonas aeruginosacan be suppressed by optimizing the administration of meropenem. However, whether the same is true forAcinetobacter baumanniiis not fully understood. We assessed the bactericidal activity of meropenem and its potency to suppress the emergence of resistance inA. baumanniiwith human simulated exposure in anin vitrointravenous-infusion hollow-fiber infection model (HFIM). Two clinical strains of carbapenem-susceptible multidrug-resistantA. baumannii(CS-MDRAB), CSRA24 and CSRA91, were used, and their MICs and mutant prevention concentrations (MPCs) were determined. Six meropenem dosage regimens (0.5, 1.0, or 2.0 g given every 8 h [q8h] with a 0.5-h or 3-h infusion for seven consecutive days) were simulated and then evaluated in the HFIM. Both the total population and resistant subpopulations of the two strains were quantified. Drug concentrations were measured by high-performance liquid chromatography. All dosage regimens, except for the lowest dosage (0.5 g for both the 0.5-h and 3-h infusions), showed 3-log CFU/ml bacterial killing. Dosage regimens of 2.0 g with 0.5-h and 3-h infusions exhibited an obvious bactericidal effect and suppressed resistance. Selective amplification of subpopulations with reduced susceptibility to meropenem was suppressed with a percentage of the dosage interval in which meropenem concentrations exceeded the MPC (T>MPC) of ≥20% or with a ratio ofT>MPC to the percentage of the dosage interval in which drug concentrations are within the mutant selection window of ≥0.25. Ourin vitrodata support the use of a high dosage of meropenem (2.0 g q8h) for the treatment of severe infection caused by CS-MDRAB.

scholarly journals Pharmacodynamic Evaluation of Plasma and Epithelial Lining Fluid Exposures of Amikacin against Pseudomonas aeruginosa in a Dynamic In Vitro Hollow-Fiber Infection Model

2020 ◽  
Vol 64 (9) ◽  
Author(s):  
Aaron J. Heffernan ◽  
Fekade B. Sime ◽  
Derek S. Sarovich ◽  
Michael Neely ◽  
Yarmarly Guerra-Valero ◽  
...  
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Hollow Fiber ◽  
Infection Model ◽  
High Dose ◽  
Epithelial Lining ◽  
Bacterial Killing ◽  
Epithelial Lining Fluid ◽  
Content Type ◽  
Initial Inoculum

ABSTRACT Given that aminoglycosides, such as amikacin, may be used for multidrug-resistant Pseudomonas aeruginosa infections, optimization of therapy is paramount for improved treatment outcomes. This study aims to investigate the pharmacodynamics of different simulated intravenous amikacin doses on susceptible P. aeruginosa to inform ventilator-associated pneumonia (VAP) and sepsis treatment choices. A hollow-fiber infection model with two P. aeruginosa isolates (MICs of 2 and 8 mg/liter) with an initial inoculum of ∼108 CFU/ml was used to test different amikacin dosing regimens. Three regimens (15, 25, and 50 mg/kg) were tested to simulate a blood exposure, while a 30 mg/kg regimen simulated the epithelial lining fluid (ELF) for potential respiratory tract infection. Data were described using a semimechanistic pharmacokinetic/pharmacodynamic (PK/PD) model. Whole-genome sequencing was used to identify mutations associated with resistance emergence. While bacterial density was reduced by >6 logs within the first 12 h in simulated blood exposures following this initial bacterial kill, there was amplification of a resistant subpopulation with ribosomal mutations that were likely mediating amikacin resistance. No appreciable bacterial killing occurred with subsequent doses. There was less (<5 log) bacterial killing in the simulated ELF exposure for either isolate tested. Simulation studies suggested that a dose of 30 and 50 mg/kg may provide maximal bacterial killing for bloodstream and VAP infections, respectively. Our results suggest that amikacin efficacy may be improved with the use of high-dose therapy to rapidly eliminate susceptible bacteria. Subsequent doses may have reduced efficacy given the rapid amplification of less-susceptible bacterial subpopulations with amikacin monotherapy.

scholarly journals Relationship between Gepotidacin Exposure and Prevention of On-Therapy Resistance Amplification in a Neisseria gonorrhoeae Hollow-Fiber In Vitro Infection Model

2020 ◽  
Vol 64 (10) ◽  
Author(s):  
Brian D. VanScoy ◽  
Nicole E. Scangarella-Oman ◽  
Steven Fikes ◽  
Sharon Min ◽  
Jianzhong Huang ◽  
...  
Keyword(s):  
Neisseria Gonorrhoeae ◽  
Hollow Fiber ◽  
Therapy Resistance ◽  
Model System ◽  
Bacterial Density ◽  
Infection Model ◽  
Drug Resistant ◽  
Content Type ◽  
Drug Concentrations

ABSTRACT Multidrug-resistant Neisseria gonorrhoeae has emerged as a threat to global health. The relationship between gepotidacin exposure and prevention of on-therapy amplification of drug-resistant N. gonorrhoeae was examined using a 7-day hollow-fiber in vitro infection model. The study design included both inactive (no-treatment and ciprofloxacin) and active (ceftriaxone) control regimens. Study drug concentration-time profiles were simulated in the in vitro system for a single oral 0.5 g ciprofloxacin dose, a single intramuscular 0.25 g ceftriaxone dose, and single or two (8 to 12 h apart) oral gepotidacin doses ranging from 0.75 to 12 g. The initial bacterial burden inoculated in the model was 106 CFU/ml. The gepotidacin, ciprofloxacin, and ceftriaxone broth MIC values for the challenge isolate (N. gonorrhoeae GSK #8) were 0.5, 2, and 0.002 mg/liter, respectively. Samples were collected for enumeration of total and drug-resistant bacterial populations and drug concentrations. The no-treatment control reached a bacterial density greater than 108 CFU/ml over 24 h and remained consistent over the 7-day study period. The bacterial density in the model system of the ciprofloxacin regimen matched that of the growth control throughout the study duration, while the ceftriaxone regimen sterilized the model system by the end of day 1. For gepotidacin, a full dose-response relationship was observed. While failure was observed for the 0.75-, 1.5-, and 3-g single-dose regimens, all gepotidacin single- or divided-dose regimens totaling at least 4.5 g prevented resistance amplification and sterilized the model system. These data are useful to provide gepotidacin dose selection support for treating patients with gonorrhea infections.

scholarly journals Effect of Moxifloxacin plus Pretomanid against Mycobacterium tuberculosis in Log Phase, Acid Phase, and Nonreplicating-Persister Phase in an In Vitro Assay

2018 ◽  
Vol 63 (1) ◽  
Author(s):  
Carolina de Miranda Silva ◽  
Amirhossein Hajihosseini ◽  
Jenny Myrick ◽  
Jocelyn Nole ◽  
Arnold Louie ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Animal Studies ◽  
Screening Strategy ◽  
Infection Model ◽  
Logarithmic Growth Phase ◽  
Vitro Assay ◽  
Content Type ◽  
Successful Approach ◽  
Resistant Strains

ABSTRACT Combination therapy is a successful approach to treat tuberculosis in patients with susceptible strains of Mycobacterium tuberculosis. However, the emergence of resistant strains requires identification of new, effective therapies. Pretomanid (PA824) and moxifloxacin (MXF) are promising options currently under evaluation in clinical trials for the treatment of susceptible and resistant mycobacteria. We applied our recently described screening strategy to characterize the interaction between PA824 and MXF toward the killing of M. tuberculosis in logarithmic growth phase (log phase), acid phase, and nonreplicating-persister (NRP) phase. Respective in vitro data generated for the H37Rv and 18b strains were evaluated in a microdilution plate system containing both drugs in combination. The Universal Response Surface Approach model from Greco et al. (W. R. Greco, G. Bravo, and J. C. Parsons, Pharmacol Rev 47:331–385, 1995) was used to characterize the nature of the interaction between both drugs; synergistic or additive combinations would prompt additional evaluation in the hollow-fiber infection model (HFIM) and in animal studies. The interaction between MXF and PA824 was additive against M. tuberculosis organisms in acid phase (interaction parameter [α] = 5.56e−8 [95% confidence interval {CI} = −0.278 to 0.278] and α = 0.408 [95% CI = 0.105 to 0.711], respectively), NRP phase (α = 0.625 [95% CI = −0.556 to 1.81] and α = 2.92 [95% CI = 0.215 to 5.63], respectively), and log phase (α = 1.57e−6 [95% CI = −0.930 to 0.930] and α = 1.83e−6 [95% CI = −0.929 and 0.929], respectively), prompting further testing of this promising combination for the treatment of tuberculosis in the HFIM and in animal studies.

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