scholarly journals In Vitro and In Vivo Pharmacokinetics-Pharmacodynamics of GV143253A, a Novel Trinem

2003 ◽  
Vol 47 (2) ◽  
pp. 770-776 ◽  
Author(s):  
Livia Ferrari ◽  
Laura Iavarone ◽  
Simone Braggio ◽  
Enza Di Modugno
Keyword(s):  
Pharmacokinetic Profile ◽  
Multidrug Resistant ◽  
Response Curves ◽  
Bacterial Killing ◽  
Dosing Interval ◽  
Human Pharmacokinetic ◽  
Dosing Regimens ◽  
Immunocompetent Mice

ABSTRACT The aim of the present study was to characterize the pharmacokinetic-pharmacodynamic relationship of GV143253A, a novel trinem anti-methicillin-resistant Staphylococcus aureus (MRSA) agent active against gram-positive cocci, including multidrug-resistant clinical isolates. An in vitro pharmacodynamic study with methicillin-susceptible S. aureus (MSSA) and MRSA has shown that the duration of exposure to GV143253A rather than its concentration is the major determinant of the extent of bacterial killing. The in vitro findings were confirmed by use of a neutropenic murine model of thigh infection caused by MSSA ATCC 25923. From the dose-response curves, the static doses extrapolated for three different dosing intervals showed that more frequent dosing of GV143253A was more effective than less frequent dosing. A pharmacokinetic-pharmacodynamic analysis demonstrated that only the time during which the drug concentration exceeded the MIC (t>MIC) correlated with in vivo GV143253A activity. The value of t>MIC required to achieve a bacteriostatic effect in a thigh infection of neutropenic animals was 20% (95% confidence interval [CI], 18 to 22%) of the dosing interval. This result is similar to those reported in the literature for carbapenems and for GV104326A, another novel trinem compound. In addition, in order to compare the therapeutic efficacy of GV143253A to that of vancomycin in a thigh infection caused by MRSA in immunocompetent mice, suitable dosing regimens were designed on the basis of previous pharmacokinetic-pharmacodynamic findings for GV143253A and on the human pharmacokinetic profile of the glycopeptide. Although the pharmacokinetic profiles of the two agents were completely different, GV143253A showed good efficacy comparable to that of vancomycin, reducing by 4 log units the bacterial counts in the thighs of treated mice relative to untreated infected animals after 48 h of therapy. The results suggest that if the time of exposure to the pathogen above the MIC is at least 30% of the dosing interval, GV143253A could have a role in the clinical treatment of infections caused by MRSA, which is difficult to eradicate with current antibiotics.

scholarly journals Prediction of Human Pharmacokinetic Profiles of the Anti-tuberculosis Drug Delamanid from Nonclinical Data: Potential Therapeutic Value Against Extrapulmonary Tuberculosis

2021 ◽  
Author(s):  
Masakazu Shibata ◽  
Masatoshi Masuda ◽  
Katsunori Sasahara ◽  
Hiroyuki Sasabe ◽  
Tomohiro Sasaki ◽  
...  
Keyword(s):  
Steady State ◽  
Allometric Scaling ◽  
Extrapulmonary Tuberculosis ◽  
Pharmacokinetic Profile ◽  
Multidrug Resistant ◽  
Pbpk Modeling ◽  
Human Pharmacokinetic ◽  
Time Courses

Delamanid has been studied extensively and approved for the treatment of pulmonary multidrug-resistant tuberculosis; however, its potential in the treatment of extrapulmonary tuberculosis remains unknown. We previously reported that in rats, delamanid was broadly distributed to various tissues in addition to the lungs. In this study, we simulated human plasma concentration–time courses (pharmacokinetic profile) of delamanid, which has a unique property of metabolism by albumin, using two different approaches (steady-state concentration of plasma-mean residence time [C ss -MRT] and physiologically based pharmacokinetic [PBPK] modeling). In C ss -MRT, allometric scaling predicted the distribution volume at steady state based on data from mice, rats, and dogs. Total clearance was predicted by in vitro – in vivo extrapolation using a scaled albumin amount. A simulated human pharmacokinetic profile using a combination of human predicted C ss and MRT was almost identical to the observed profile after single oral administration, which suggests that the pharmacokinetic profile of delamanid could be predicted by allometric scaling from these animals and metabolic capacity in vitro . The PBPK model was constructed on the assumption that delamanid was metabolized by albumin in circulating plasma and tissues; to which, the simulated pharmacokinetic profile was consistent. Moreover, the PBPK modeling approach demonstrated that the simulated concentrations of delamanid at steady state in the lung, brain, liver, and heart were higher than the in vivo effective concentration for Mycobacterium tuberculosis . These results indicate that delamanid may achieve similar concentrations in various organs to that of the lung and may have the potential to treat extrapulmonary tuberculosis.

scholarly journals Polymyxin Triple Combinations against Polymyxin-Resistant, Multidrug-Resistant, KPC-Producing Klebsiella pneumoniae

2020 ◽  
Vol 64 (8) ◽  
Author(s):  
Su Mon Aye ◽  
Irene Galani ◽  
Heidi Yu ◽  
Jiping Wang ◽  
Ke Chen ◽  
...  
Keyword(s):  
Klebsiella Pneumoniae ◽  
Triple Therapy ◽  
Polymyxin B ◽  
Multidrug Resistant ◽  
Infection Model ◽  
Bacterial Killing ◽  
Standard Dosage ◽  
Time Kill

ABSTRACT Resistance to polymyxin antibiotics is increasing. Without new antibiotic classes, combination therapy is often required. We systematically investigated bacterial killing with polymyxin-based combinations against multidrug-resistant (including polymyxin-resistant), carbapenemase-producing Klebsiella pneumoniae. Monotherapies and double- and triple-combination therapies were compared to identify the most efficacious treatment using static time-kill studies (24 h, six isolates), an in vitro pharmacokinetic/pharmacodynamic model (IVM; 48 h, two isolates), and the mouse thigh infection model (24 h, six isolates). In static time-kill studies, all monotherapies (polymyxin B, rifampin, amikacin, meropenem, or minocycline) were ineffective. Initial bacterial killing was enhanced with various polymyxin B-containing double combinations; however, substantial regrowth occurred in most cases by 24 h. Most polymyxin B-containing triple combinations provided greater and more sustained killing than double combinations. Standard dosage regimens of polymyxin B (2.5 mg/kg of body weight/day), rifampin (600 mg every 12 h), and amikacin (7.5 mg/kg every 12 h) were simulated in the IVM. Against isolate ATH 16, no viable bacteria were detected across 5 to 25 h with triple therapy, with regrowth to ∼2-log10 CFU/ml occurring at 48 h. Against isolate BD 32, rapid initial killing of ∼3.5-log10 CFU/ml at 5 h was followed by a slow decline to ∼2-log10 CFU/ml at 48 h. In infected mice, polymyxin B monotherapy (60 mg/kg/day) generally was ineffective. With triple therapy (polymyxin B at 60 mg/kg/day, rifampin at 120 mg/kg/day, and amikacin at 300 mg/kg/day), at 24 h there was an ∼1.7-log10 CFU/thigh reduction compared to the starting inoculum for all six isolates. Our results demonstrate that the polymyxin B-rifampin-amikacin combination significantly enhanced in vitro and in vivo bacterial killing, providing important information for the optimization of polymyxin-based combinations in patients.

scholarly journals In VitroandIn VivoActivities of the Nitroimidazole TBA-354 against Mycobacterium tuberculosis

2014 ◽  
Vol 59 (1) ◽  
pp. 136-144 ◽  
Author(s):  
A. M. Upton ◽  
S. Cho ◽  
T. J. Yang ◽  
Y. Kim ◽  
Y. Wang ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Pharmacokinetic Profile ◽  
Multidrug Resistant ◽  
Phase Iii ◽  
Drug Resistant ◽  
Next Generation ◽  
Content Type ◽  
Resistant Tuberculosis

ABSTRACTNitroimidazoles are a promising new class of antitubercular agents. The nitroimidazo-oxazole delamanid (OPC-67683, Deltyba) is in phase III trials for the treatment of multidrug-resistant tuberculosis, while the nitroimidazo-oxazine PA-824 is entering phase III for drug-sensitive and drug-resistant tuberculosis. TBA-354 (SN31354[(S)-2-nitro-6-((6-(4-trifluoromethoxy)phenyl)pyridine-3-yl)methoxy)-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine]) is a pyridine-containing biaryl compound with exceptional efficacy against chronic murine tuberculosis and favorable bioavailability in preliminary rodent studies. It was selected as a potential next-generation antituberculosis nitroimidazole following an extensive medicinal chemistry effort. Here, we further evaluate the pharmacokinetic properties and activity of TBA-354 againstMycobacterium tuberculosis. TBA-354 is narrow spectrum and bactericidalin vitroagainst replicating and nonreplicatingMycobacterium tuberculosis, with potency similar to that of delamanid and greater than that of PA-824. The addition of serum protein or albumin does not significantly alter this activity. TBA-354 maintains activity againstMycobacterium tuberculosisH37Rv isogenic monoresistant strains and clinical drug-sensitive and drug-resistant isolates. Spontaneous resistant mutants appear at a frequency of 3 × 10−7.In vitrostudies andin vivostudies in mice confirm that TBA-354 has high bioavailability and a long elimination half-life.In vitrostudies suggest a low risk of drug-drug interactions. Low-dose aerosol infection models of acute and chronic murine tuberculosis reveal time- and dose-dependentin vivobactericidal activity that is at least as potent as that of delamanid and more potent than that of PA-824. Its superior potency and pharmacokinetic profile that predicts suitability for once-daily oral dosing suggest that TBA-354 be studied further for its potential as a next-generation nitroimidazole.

scholarly journals Efficacy of the New Lantibiotic NAI-107 in Experimental Infections Induced by Multidrug-Resistant Gram-Positive Pathogens

2011 ◽  
Vol 55 (4) ◽  
pp. 1671-1676 ◽  
Author(s):  
Daniela Jabés ◽  
Cristina Brunati ◽  
GianPaolo Candiani ◽  
Simona Riva ◽  
Gabriella Romanó ◽  
...  
Keyword(s):  
Bactericidal Activity ◽  
Bacterial Load ◽  
Severe Infection ◽  
Multidrug Resistant ◽  
Minimal Bactericidal Concentration ◽  
Gram Positive ◽  
Immunocompetent Mice ◽  
Dose Proportional

ABSTRACTNAI-107 is a novel lantibiotic active against Gram-positive bacteria, including methicillin-resistantStaphylococcus aureus(MRSA), glycopeptide-intermediateS. aureus(GISA), and vancomycin-resistant enterococci (VRE). The aim of this study was to evaluate thein vivoefficacy of NAI-107 in animal models of severe infection. In acute lethal infections induced with a penicillin-intermediateStreptococcus pneumoniaestrain in immunocompetent mice, or with MRSA, GISA, and VRE strains in neutropenic mice, the 50% effective dose (ED50) values of NAI-107 were comparable or lower than those of reference compounds, irrespective of the strain and immune status (0.51 to 14.2 mg/kg of body weight for intravenous [i.v.] NAI-107, 5.1 to 22.4 for oral linezolid, and 22.4 for subcutaneous [s.c.] vancomycin). Inthe granuloma pouch model induced in rats with a MRSA strain, intravenous NAI-107 showed a dose-proportional bactericidal activity that, at a single 40-mg/kg dose, compared with 2 20-mg/kg doses at a 12-h or 24-h interval, caused a 3-log10-CFU/ml reduction of viable MRSA in exudates that persisted for more than 72 h. Rat endocarditis was induced with a MRSA strain and treated for five consecutive days. In a first experiment, using 5, 10, or 20 mg/kg/day, and in a second experiment, when 10 mg/kg at 12-h intervals was compared to 20 mg/kg/day, intravenous NAI-107 was effective in reducing the bacterial load in heart vegetations in a dose-proportional manner. Trough plasma levels, as determined on days 2 and 5, were several times higher than the NAI-107 minimal bactericidal concentration (MBC). NAI-107 binding to rat and human serum ranges between 93% and 98.6%. The rapid bactericidal activity of NAI-107 observedin vitrowas thus confirmed by the efficacy in several models of experimental infection induced by Gram-positive pathogens, supporting further investigation of the compound.

scholarly journals In Vivo Efficacy of Simulated Human Dosing Regimens of Prolonged-Infusion Doripenem against Carbapenemase- Producing Klebsiella pneumoniae

2010 ◽  
Vol 54 (10) ◽  
pp. 4112-4115 ◽  
Author(s):  
Catharine C. Bulik ◽  
David P. Nicolau
Keyword(s):  
Klebsiella Pneumoniae ◽  
White Blood Cells ◽  
Multidrug Resistant ◽  
Gram Negative ◽  
Wide Range ◽  
Dosing Regimens ◽  
Gram Negative Organisms ◽  
Immunocompromised Mice

ABSTRACT Carbapenemase-producing Klebsiella pneumoniae (KPC) bacteria are rapidly becoming one of the most detrimental drug-resistant Gram-negative pathogens. Doripenem is the newest FDA-approved carbapenem that has the greatest in vitro potency against a wide range of Gram-negative organisms, including multidrug-resistant organisms. Previous work in an animal model has shown efficacy against Pseudomonas aeruginosa with MICs above the current breakpoints of susceptibility. The purpose of this study is to evaluate the efficacy of 1-g and 2-g dose prolonged infusions of doripenem against KPC isolates in both an immunocompetent and neutropenic murine thigh model. Seven clinical KPC isolates (broth microdilution [BMD] MIC range, 4 to 32 μg/ml; Etest MIC range, 3 to >32 μg/ml) were used. After infection, groups of mice were administered doripenem doses previously shown to simulate the exposures observed in humans after the administration of 1 or 2 g every 8 h as a 4-h infusion. In immunocompromised mice, 1- and 2-g doses of doripenem achieved bacteriostasis against isolates with MICs up to and including 8 μg/ml and 16 μg/ml, respectively. In immunocompetent animals, statistically significant reductions in the number of CFU were observed with overall decreases of approximately 1 log (P < 0.05). While carbapenemase-producing Klebsiella pneumoniae continues to decrease our meager supply of active agents, the ability of doripenem to produce CFU reductions in the presence of white blood cells (WBCs) using humanized exposures suggests the potential utility of this agent in combination against this increasingly problematic pathogen.

scholarly journals Bactericidal Monoclonal Antibodies Specific to the Lipopolysaccharide O Antigen from Multidrug-Resistant Escherichia coli Clone ST131-O25b:H4 Elicit Protection in Mice

2015 ◽  
Vol 59 (6) ◽  
pp. 3109-3116 ◽  
Author(s):  
Valéria Szijártó ◽  
Luis M. Guachalla ◽  
Zehra C. Visram ◽  
Katharina Hartl ◽  
Cecília Varga ◽  
...  
Keyword(s):  
Escherichia Coli ◽  
Monoclonal Antibodies ◽  
Human Serum ◽  
Significant Proportion ◽  
Multidrug Resistant ◽  
Bacterial Killing ◽  
Content Type ◽  
E Coli

ABSTRACTTheEscherichia colisequence type 131 (ST131)-O25b:H4 clone has spread worldwide and become responsible for a significant proportion of multidrug-resistant extraintestinal infections. We generated humanized monoclonal antibodies (MAbs) that target the lipopolysaccharide O25b antigen conserved within this lineage. These MAbs bound to the surface of live bacterial cells irrespective of the capsular type expressed. In a serum bactericidal assayin vitro, MAbs induced >95% bacterial killing in the presence of human serum as the complement source. Protective efficacy at low antibody doses was observed in a murine model of bacteremia. The mode of actionin vivowas investigated by using aglycosylated derivatives of the protective MAbs. The significant binding to liveE. colicells and thein vitroandin vivoefficacy were corroborated in assays using bacteria grown in human serum to mimic relevant clinical conditions. Given the dry pipeline of novel antibiotics against multidrug-resistant Gram-negative pathogens, passive immunization with bactericidal antibodies offers a therapeutic alternative to control infections caused byE. coliST131-O25b:H4.

scholarly journals Bacterial Photodynamic Inactivation Mediated by Methylene Blue and Red Light Is Enhanced by Synergistic Effect of Potassium Iodide

2015 ◽  
Vol 59 (9) ◽  
pp. 5203-5212 ◽  
Author(s):  
Daniela Vecchio ◽  
Asheesh Gupta ◽  
Liyi Huang ◽  
Giacomo Landi ◽  
Pinar Avci ◽  
...  
Keyword(s):  
Methylene Blue ◽  
Potassium Iodide ◽  
Bacterial Species ◽  
Red Light ◽  
Multidrug Resistant ◽  
Photodynamic Inactivation ◽  
Bacterial Killing ◽  
Risk Of Death

ABSTRACTThe inexorable increase of antibiotic resistance occurring in different bacterial species is increasing the interest in developing new antimicrobial treatments that will be equally effective against multidrug-resistant strains and will not themselves induce resistance. One of these alternatives may be photodynamic inactivation (PDI), which uses a combination of nontoxic dyes, called photosensitizers (PS), excited by harmless visible light to generate reactive oxygen species (ROS) by type 1 (radical) and type 2 (singlet oxygen) pathways. In this study, we asked whether it was possible to improve the efficacy of PDIin vitroandin vivoby addition of the inert salt potassium iodide (KI) to a commonly investigated PS, the phenothiazinium dye methylene blue (MB). By adding KI, we observed a consistent increase of red light-mediated bacterial killing of Gram-positive and Gram-negative speciesin vitroandin vivo. In vivo, we also observed less bacterial recurrence in wounds in the days posttreatment. The mechanism of action is probably due to formation of reactive iodine species that are produced quickly with a short lifetime. This finding may have a relevant clinical impact by reducing the risk of amputation and, in some cases, the risk of death, leading to improvement in the care of patients affected by localized infections.

scholarly journals The MUT056399 Inhibitor of FabI Is a New Antistaphylococcal Compound

2011 ◽  
Vol 55 (10) ◽  
pp. 4692-4697 ◽  
Author(s):  
S. Escaich ◽  
L. Prouvensier ◽  
M. Saccomani ◽  
L. Durant ◽  
M. Oxoby ◽  
...  
Keyword(s):  
Low Frequency ◽  
Systemic Infection ◽  
Multidrug Resistant ◽  
Infection Model ◽  
Coagulase Negative Staphylococci ◽  
Content Type ◽  
Immunocompetent Mice ◽  
Novel Drug

ABSTRACTMUT056399 is a highly potent new inhibitor of the FabI enzyme of bothStaphylococcus aureusandEscherichia coli. In vitro, MUT056399 was very active againstS. aureusstrains, including methicillin-susceptibleS. aureus(MSSA), methicillin-resistantS. aureus(MRSA), linezolid-resistant, and multidrug-resistant strains, with MIC90s between 0.03 and 0.12 μg/ml. MUT056399 was also active against coagulase-negative staphylococci, with MIC90s between 0.12 and 4 μg/ml. The antibacterial spectrum is consistent with specific FabI inhibition with no activity against bacteria using FabK but activity against FabI-containing Gram-negative bacilli.In vitro, resistant clones ofS. aureuswere obtained at a low frequency. All of the resistant clones analyzed were found to contain mutations in thefabIgene.In vivo, MUT056399, administered subcutaneously, protected mice from a lethal systemic infection induced by MSSA, MRSA, and vancomycin-intermediateS. aureusstrains (50% effective doses ranging from 19.3 mg/kg/day to 49.6 mg/kg/day). In the nonneutropenic murine thigh infection model, the same treatment with MUT056399 reduced the bacterial multiplication of MSSA and MRSA in the thighs of immunocompetent mice. These properties support MUT056399 as a very promising candidate for a novel drug to treat severe staphylococcal infections.

scholarly journals Development and validation of an in vivo model for pharmacokinetic/pharmacodynamic studies of antimicrobials in domestic animals

2012 ◽  
Vol 2 (1) ◽  
pp. 10
Author(s):  
Maria Laura Meneses ◽  
Gabriela Albarellos ◽  
Maria Fabiana Landoni
Keyword(s):  
Animal Species ◽  
Bacterial Resistance ◽  
Inhibitory Concentration ◽  
Pharmacokinetic Profile ◽  
In Vivo Model ◽  
Subcutaneous Implantation ◽  
Bacterial Killing ◽  
Development And Validation

The increase in bacterial resistance to antimicrobials has motivated researchers to develop experimental animal models to integrate pharmacokinetic/pharmacodynamic (PK/ PD) profiles to predict the effectiveness of antimicrobials treatments. The models used to date have a weakness based on the use of the minimum inhibitory concentration (MIC), whose value is obtained only <em>in vitro</em>, determined under constant conditions with an exponential error, regarding to the double dilution used. The aim of this study was to develop and validate a device for subcutaneous implantation, which can be applied in any animal species, allowing simultaneous description of <em>in vivo</em> bacterial killing curve and pharmacokinetic profile of the drug under study. Based on the obtained results, it can be concluded that the use of this model will allow researchers to apply PK/ PD decreasing the error originated in the use of MIC as a measure of antimicrobial pharmacodynamics.

scholarly journals Use of Carbapenems against Clinical, Nontyphoid Salmonella Isolates: Results fromIn VitroandIn VivoAnimal Studies

2012 ◽  
Vol 56 (6) ◽  
pp. 2916-2922 ◽  
Author(s):  
Hung-Jen Tang ◽  
Chi-Chung Chen ◽  
Chun-Cheng Zhang ◽  
Kuo Chen Cheng ◽  
Shyh-Ren Chiang ◽  
...  
Keyword(s):  
Ex Vivo ◽  
Survival Rates ◽  
Pharmacokinetic Profile ◽  
Multidrug Resistant ◽  
Time Curve ◽  
Content Type ◽  
Percent Time ◽  
Clinical Investigations

ABSTRACTThe emergence of multidrug-resistantSalmonellaisolates has created the need for new therapeutic agents. We evaluated the intracellular activity of four carbapenem compounds against clinical nontyphoidSalmonella(NTS) isolatesin vitroandex vivo. Subsequently, the efficacy of carbapenem treatment against selectedSalmonellaisolatesin vivowas assessed using a murine peritonitis model. The MIC50and MIC90for doripenem, ertapenem, imipenem, and meropenem against 126 NTS isolates were found to be 0.062 and 0.062, 0.015 and 0.015, 0.5 and 1, and 0.031 and 0.031 μg/ml, respectively. The intracellular killing effect of ertapenem was sustained for 24 h and was superior to that of imipenem, meropenem, and doripenem; its effect was comparable to that of ceftriaxone. Ertapenem demonstrated an excellent pharmacokinetic profile with a percent time above the MIC of 75.5% and an area under the concentration-time curve/MIC ratio of 20,733. When peritoneal exudate cells were examined directlyex vivofrom mice withSalmonella-induced peritonitis, cells from mice treated with ertapenem and ceftriaxone had intracellular and extracellular bacterial counts reduced 102- to 104-fold and exhibited killing effects similar to each other. The survival rates of mice inoculated with 1 × 105and 106CFU of a ceftriaxone-susceptibleSalmonellaisolate that were subsequently treated with ertapenem or ceftriaxone were 100% and 90%, respectively. When mice were inoculated with 5 × 104and 105CFU of a ceftriaxone-resistant and ciprofloxacin-resistantSalmonellaisolate, mice treated with ertapenem had a higher survival rate than mice treated with ceftriaxone (70% versus 0% and 50% versus 0%, respectively;P< 0.001). Our results suggest that ertapenem is at least as effective as ceftriaxone in treating murineSalmonellainfections and show that further clinical investigations on the potential use of ertapenem in treatment of humanSalmonellainfections are warranted.

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