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 Low-dose aerosol infection model for testing drugs for efficacy against Mycobacterium tuberculosis.

1996 ◽  
Vol 40 (12) ◽  
pp. 2809-2812 ◽  
Author(s):  
B P Kelly ◽  
S K Furney ◽  
M T Jessen ◽  
I M Orme
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Low Dose ◽  
Bacterial Load ◽  
Lung Model ◽  
Exposure Model ◽  
Infection Model ◽  
High Dose ◽  
Level Of Activity ◽  
Days Of Therapy ◽  
Aerosol Infection

As a paradigm for chronic infectious diseases, tuberculosis exhibits a variety of clinical presentations, ranging from primary pulmonary tuberculosis to reactivation tuberculosis and cavitary disease. To date, the animal models used in evaluating chemotherapy of tuberculosis have been high-dose intravenous models that mimic the disseminated forms of the disease. In the present study, we have used a low-dose aerosol exposure model which we feel better reflects newly diagnosed tuberculosis in patients converting to tuberculin positivity. As appropriate examples of chemotherapy, four rifamycins (rifampin, rifabutin, rifapentine, and KRM-1648) were tested, first in an in vitro murine macrophage model and then in the low-dose aerosol infection model, for their activity against Mycobacterium tuberculosis. In both models, KRM-1648 had the highest level of activity of the four compounds. In the infected-lung model, rifabutin, rifapentine, and KRM-1648 all had sterilizing activity when given orally at 5 mg/kg of body weight per day. When given at 2.5 mg/kg/day, KRM-1648 had the highest level of activity of the four drugs, reducing the bacterial load by 2.7 logs over 35 days of therapy.

scholarly journals Generic Vancomycin Enriches Resistant Subpopulations of Staphylococcus aureus after Exposure in a Neutropenic Mouse Thigh Infection Model

2011 ◽  
Vol 56 (1) ◽  
pp. 243-247 ◽  
Author(s):  
Carlos A. Rodriguez ◽  
Maria Agudelo ◽  
Andres F. Zuluaga ◽  
Omar Vesga
Keyword(s):  
Staphylococcus Aureus ◽  
Population Analysis ◽  
Recovery Process ◽  
Control Group ◽  
Infection Model ◽  
Content Type ◽  
Sterile Saline ◽  
Generic Products ◽  
The Impact

ABSTRACTPrevious studies have shown that “bioequivalent” generic products of vancomycin are less effectivein vivoagainstStaphylococcus aureusthan the innovator compound. Considering that suboptimal bactericidal effect has been associated with emergence of resistance, we aimed to assessin vivothe impact of exposure to innovator and generic products of vancomycin onS. aureussusceptibility. A clinical methicillin-resistantS. aureus(MRSA) strain from a liver transplant patient with persistent bacteremia was used for which MIC, minimum bactericidal concentration (MBC), and autolytic properties were determined. Susceptibility was also assessed by determining a population analysis profile (PAP) with vancomycin concentrations from 0 to 5 mg/liter. ICR neutropenic mice were inoculated in each thigh with ∼7.0 log10CFU. Treatment with the different vancomycin products (innovator and three generics; 1,200 mg/kg of body weight/day every 3 h) started 2 h later while the control group received sterile saline. After 24 h, mice were euthanized, and the thigh homogenates were plated. Recovered colonies were reinoculated to new groups of animals, and the exposure-recovery process was repeated until 12 cycles were completed. The evolution of resistance was assessed by PAP after cycles 5, 10, 11, and 12. The initial isolate displayed reduced autolysis and higher resistance frequencies thanS. aureusATCC 29213 but without vancomycin-intermediateS. aureus(VISA) subpopulations. After 12 cycles, innovator vancomycin had significantly reduced resistant subpopulations at 1, 2, and 3 mg/liter, while the generic products had enriched them progressively by orders of magnitude. The great capacity of generic vancomycin to select for less susceptible organisms raises concerns about the role of therapeutic inequivalence of any antimicrobial on the epidemiology of resistance worldwide.

scholarly journals Population Pharmacokinetic/Pharmacodynamic Analysis of the Bactericidal Activities of Sutezolid (PNU-100480) and Its Major Metabolite against Intracellular Mycobacterium tuberculosis inEx VivoWhole-Blood Cultures of Patients with Pulmonary Tuberculosis

2014 ◽  
Vol 58 (6) ◽  
pp. 3306-3311 ◽  
Author(s):  
Tong Zhu ◽  
Sven O. Friedrich ◽  
Andreas Diacon ◽  
Robert S. Wallis
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Hollow Fiber ◽  
Ex Vivo ◽  
Parent Compound ◽  
Plasma Concentrations ◽  
Population Pharmacokinetic ◽  
Model Parameters ◽  
Data Set ◽  
Content Type

ABSTRACTSutezolid (PNU-100480 [U-480]) is an oxazolidinone antimicrobial being developed for the treatment of tuberculosis. An active sulfoxide metabolite (PNU-101603 [U-603]), which reaches concentrations in plasma several times those of the parent, has been reported to drive the killing of extracellularMycobacterium tuberculosisby sutezolid in hollow-fiber culture. However, the relative contributions of the parent and metabolite against intracellularM. tuberculosisin vivoare not fully understood. The relationships between the plasma concentrations of U-480 and U-603 and intracellular whole-blood bactericidal activity (WBA) inex vivocultures were examined using a direct competitive population pharmacokinetic (PK)/pharmacodynamic 4-parameter sigmoid model. The data set included 690 PK determinations and 345 WBA determinations from 50 tuberculosis patients enrolled in a phase 2a sutezolid trial. The model parameters were solved iteratively. The median U-603/U-480 concentration ratio was 7.1 (range, 1 to 28). The apparent 50% inhibitory concentration of U-603 for intracellularM. tuberculosiswas 17-fold greater than that of U-480 (90% confidence interval [CI], 9.9- to 53-fold). Model parameters were used to simulatein vivoactivity after oral dosing with sutezolid at 600 mg twice a day (BID) and 1,200 mg once a day (QD). Divided dosing resulted in greater cumulative activity (−0.269 log10per day; 90% CI, −0.237 to −0.293 log10per day) than single daily dosing (−0.186 log10per day; 90% CI, −0.160 to −0.208 log10per day). U-480 accounted for 84% and 78% of the activity for BID and QD dosing, respectively, despite the higher concentrations of U-603. Killing of intracellularM. tuberculosisby orally administered sutezolid is mainly due to the activity of the parent compound. Taken together with the findings of other studies in the hollow-fiber model, these findings suggest that sutezolid and its metabolite act on different mycobacterial subpopulations.

scholarly journals The Combination of Rifampin plus Moxifloxacin Is Synergistic for Suppression of Resistance but Antagonistic for Cell Kill of Mycobacterium tuberculosis as Determined in a Hollow-Fiber Infection Model

mBio ◽  
2010 ◽  
Vol 1 (3) ◽  
Author(s):  
G. L. Drusano ◽  
Nicole Sgambati ◽  
Adam Eichas ◽  
David L. Brown ◽  
Robert Kulawy ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Combination Therapy ◽  
Hollow Fiber ◽  
Bacterial Cell ◽  
Infection Model ◽  
Bacterial Burden ◽  
Log Reduction ◽  
Significant Difference ◽  
Cell Kill ◽  
The Impact

ABSTRACTMoxifloxacin is under development for expanded use againstMycobacterium tuberculosis. Rifampin is a mainstay of therapy. We examined the interaction of moxifloxacin plus rifampin for log-phase and nonreplicating persister (NRP) organisms. For this evaluation, we employed our hollow-fiber infection model, in which organisms are exposed to clinically relevant drug concentration-time profiles and the impact on bacterial cell kill and resistant subpopulation amplification is determined. In log phase, resistance emergence was observed in all monotherapy regimens and in no combination therapy regimen. No difference was seen in time to a 3-log reduction in the bacterial burden; there was a significant difference in time to resistance emergence (P= 0.0006). In the NRP experiment, no resistance emergence was seen. There was a significant difference between the monotherapy and combination therapy regimens in time to a 3-log reduction in the bacterial burden (P= 0.042). The combination is efficacious for suppressing resistant organisms but is antagonistic for cell kill.IMPORTANCEM. tuberculosisinfects one-third of the world’s population. Multiresistant organisms have become more frequent, threatening our ability to provide adequate chemotherapy. Moxifloxacin has been seen as an important new agent with the potential to supplant isoniazid or add to the rifampin/isoniazid combination.M. tuberculosisalso exists in different physiological states, including the NRP phenotype. We examined the moxifloxacin/rifampin combination in a newin vitrosystem to allow judgment of how moxifloxacin would interact with rifampin and allow its performance in clinical trials to be placed into perspective. Importantly, the combination suppressed resistance emergence, but at the price of slightly slowing bacterial cell kill. This new combination is a welcome addition to the physician’s armamentarium.

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 In Vitro and In Vivo Activities of the Riminophenazine TBI-166 against Mycobacterium tuberculosis

2019 ◽  
Vol 63 (5) ◽  
Author(s):  
Jian Xu ◽  
Bin Wang ◽  
Lei Fu ◽  
Hui Zhu ◽  
Shaochen Guo ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Skin Pigmentation ◽  
Multidrug Resistant ◽  
Content Type ◽  
Resistant Tuberculosis ◽  
Wild Strains ◽  
Skin Discoloration ◽  
Aerosol Infection

ABSTRACT The riminophenazine agent clofazimine (CFZ) is repurposed as an important component of the new short-course multidrug-resistant tuberculosis regimen and significantly shortens first-line regimen for drug-susceptible tuberculosis in mice. However, CFZ use is hampered by its unwelcome skin discoloration in patients. A new riminophenazine analog, TBI-166, was selected as a potential next-generation antituberculosis riminophenazine following an extensive medicinal chemistry effort. Here, we evaluated the activity of TBI-166 against Mycobacterium tuberculosis and its potential to accumulate and discolor skin. The in vitro activity of TBI-166 against both drug-sensitive and drug-resistant M. tuberculosis is more potent than that of CFZ. Spontaneous mutants resistant to TBI-166 were found at a frequency of 2.3 × 10−7 in wild strains of M. tuberculosis. TBI-166 demonstrates activity at least equivalent to that of CFZ against intracellular M. tuberculosis and in low-dose aerosol infection models of acute and chronic murine tuberculosis. Most importantly, TBI-166 causes less skin discoloration than does CFZ despite its higher tissue accumulation. The efficacy of TBI-166, along with its decreased skin pigmentation, warrants further study and potential clinical use.

scholarly journals In Vitro and In Vivo Activities of Macrolide Derivatives against Mycobacterium tuberculosis

2005 ◽  
Vol 49 (4) ◽  
pp. 1447-1454 ◽  
Author(s):  
Kanakeshwari Falzari ◽  
Zhaohai Zhu ◽  
Dahua Pan ◽  
Huiwen Liu ◽  
Poonpilas Hongmanee ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Vero Cells ◽  
Infection Model ◽  
Gram Positive Bacteria ◽  
Fold Reduction ◽  
Dependent Inhibition ◽  
Low Cytotoxicity ◽  
Aerosol Infection

ABSTRACTExisting macrolides have never shown definitive clinical efficacy in tuberculosis. Recent reports suggest that ribosome methylation is involved in macrolide resistance inMycobacterium tuberculosis, a mechanism that newer macrolides have been designed to overcome in gram-positive bacteria. Therefore, selected macrolides and ketolides (descladinose) with substitutions at positions 9, 11,12, and 6 were assessed for activity againstM. tuberculosis, and those with MICs of ≤4 μM were evaluated for cytotoxicity to Vero cells and J774A.1 macrophages. Several compounds with 9-oxime substitutions or aryl substitutions at position 6 or on 11,12 carbamates or carbazates demonstrated submicromolar MICs. For the three macrolide-ketolide pairs, macrolides demonstrated superior activity. Four compounds with low MICs and low cytotoxicity also effected significant reductions in CFU in infected macrophages. Active compounds were assessed for tolerance and the ability to reduce CFU in the lungs of BALB/c mice in an aerosol infection model. A substituted 11,12 carbazate macrolide demonstrated significant dose-dependent inhibition ofM. tuberculosisgrowth in mice, with a 10- to 20-fold reduction of CFU in lung tissue. Structure-activity relationships, some of which are unique toM. tuberculosis, suggest several synthetic directions for further improvement of antituberculosis activity. This class appears promising for yielding a clinically useful agent for tuberculosis.

scholarly journals Linezolid Kills Acid-Phase and Nonreplicative-Persister-Phase Mycobacterium tuberculosis in a Hollow-Fiber Infection Model

2018 ◽  
Vol 62 (8) ◽  
Author(s):  
G. L. Drusano ◽  
Jenny Myrick ◽  
Michael Maynard ◽  
Jocelyn Nole ◽  
Brandon Duncanson ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Hollow Fiber ◽  
Infection Model ◽  
Phase Growth ◽  
Minimum Concentration ◽  
Once Daily ◽  
Content Type ◽  
Metabolic States ◽  
Daily Dose ◽  
Clear Dose Response

ABSTRACT The therapy for treatment of Mycobacterium tuberculosis infections is long and arduous. It has been hypothesized that the therapy duration is driven primarily by populations of organisms in different metabolic states that replicate slowly or not at all (acid-phase and nonreplicative-persister [NRP]-phase organisms). Linezolid is an oxazolidinone antimicrobial with substantial activity against Log-phase M. tuberculosis. Here, we examined organisms in acid-phase growth and nonreplicative-persister-phenotype growth and determined the effect of differing clinically relevant exposures to linezolid in a hollow-fiber infection model (HFIM). The endpoints measured were bacterial kill over 29 days and whether organisms that were less susceptible to linezolid could be recovered during that period. In addition, we evaluated the effect of administration schedule on linezolid activity, contrasting daily administration with administration of twice the daily dose every other day. Linezolid demonstrated robust activity when administered daily against both acid-phase and NRP-phase organisms. We demonstrated a clear dose response, with 900 mg of linezolid daily generating ≥3 Log(CFU/ml) killing of acid-phase and NRP-phase M. tuberculosis over 29 days. Amplification of a population less susceptible to linezolid was not seen. Activity was reduced with every 48-h dosing, indicating that the minimum concentration (Cmin)/MIC ratio drove the microbiological effect. We conclude that once-daily linezolid dosing has substantial activity against M. tuberculosis in acid-phase and NRP-phase metabolic states. Other studies have shown activity against Log-phase M. tuberculosis. Linezolid is a valuable addition to the therapeutic armamentarium for M. tuberculosis and has the potential for substantially shortening therapy duration.

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 In VivoEfficacy of Anuran Trypsin Inhibitory Peptides against Staphylococcal Skin Infection and the Impact of Peptide Cyclization

2015 ◽  
Vol 59 (4) ◽  
pp. 2113-2121 ◽  
Author(s):  
U. Malik ◽  
O. N. Silva ◽  
I. C. M. Fensterseifer ◽  
L. Y. Chan ◽  
R. J. Clark ◽  
...  
Keyword(s):  
Antimicrobial Agents ◽  
Cyclic Peptide ◽  
Sequence Similarity ◽  
Infection Model ◽  
Content Type ◽  
Wide Range ◽  
Inhibitory Activities ◽  
The Impact

ABSTRACTStaphylococcus aureusis a virulent pathogen that is responsible for a wide range of superficial and invasive infections. Its resistance to existing antimicrobial drugs is a global problem, and the development of novel antimicrobial agents is crucial. Antimicrobial peptides from natural resources offer potential as new treatments against staphylococcal infections. In the current study, we have examined the antimicrobial properties of peptides isolated from anuran skin secretions and cyclized synthetic analogues of these peptides. The structures of the peptides were elucidated by nuclear magnetic resonance (NMR) spectroscopy, revealing high structural and sequence similarity with each other and with sunflower trypsin inhibitor 1 (SFTI-1). SFTI-1 is an ultrastable cyclic peptide isolated from sunflower seeds that has subnanomolar trypsin inhibitory activity, and this scaffold offers pharmaceutically relevant characteristics. The five anuran peptides were nonhemolytic and noncytotoxic and had trypsin inhibitory activities similar to that of SFTI-1. They demonstrated weakin vitroinhibitory activities againstS. aureus, but several had strong antibacterial activities againstS. aureusin anin vivomurine wound infection model. pYR, an immunomodulatory peptide fromRana sevosa, was the most potent, with complete bacterial clearance at 3 mg · kg−1. Cyclization of the peptides improved their stability but was associated with a concomitant decrease in antimicrobial activity. In summary, these anuran peptides are promising as novel therapeutic agents for treating infections from a clinically resistant pathogen.

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