scholarly journals Selection of a Moxifloxacin Dose That Suppresses Drug Resistance inMycobacterium tuberculosis,by Use of an In Vitro Pharmacodynamic Infection Model and Mathematical Modeling

2004 ◽  
Vol 190 (9) ◽  
pp. 1642-1651 ◽  
Author(s):  
Tawanda Gumbo ◽  
Arnold Louie ◽  
Mark R. Deziel ◽  
Linda M. Parsons ◽  
Max Salfinger ◽  
...  
Keyword(s):  
Mathematical Modeling ◽  
Drug Resistance ◽  
Infection Model ◽  
Selection Of

scholarly journals Relationship between Ceftolozane-Tazobactam Exposure and Drug Resistance Amplification in a Hollow-Fiber Infection Model

2013 ◽  
Vol 57 (9) ◽  
pp. 4134-4138 ◽  
Author(s):  
Brian VanScoy ◽  
Rodrigo E. Mendes ◽  
Mariana Castanheira ◽  
Jennifer McCauley ◽  
Sujata M. Bhavnani ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Hollow Fiber ◽  
Drug Exposure ◽  
Resistant Bacteria ◽  
Infection Model ◽  
Drug Resistant ◽  
Dose Ratio ◽  
Bacterial Drug Resistance ◽  
Dosing Regimens ◽  
Selection Of

ABSTRACTIn an era of rapidly emerging antimicrobial-resistant bacteria, it is critical to understand the importance of the relationships among drug exposure, duration of therapy, and selection of drug resistance. Herein we describe the results of studies designed to determine the ceftolozane-tazobactam exposure necessary to prevent the amplification of drug-resistant bacterial subpopulations in a hollow-fiber infection model. The challenge isolate was a CTX-M-15-producingEscherichia coliisolate genetically engineered to transcribe a moderate level ofblaCTX-M-15. This organism'sblaCTX-M-15transcription level was confirmed by relative quantitative reverse transcription-PCR (qRT-PCR), β-lactamase hydrolytic assays, and a ceftolozane MIC value of 16 mg/liter. In these studies, the experimental duration (10 days), ceftolozane-tazobactam dose ratio (2:1), and dosing interval (every 8 h) were selected to approximate those expected to be used clinically. The ceftolozane-tazobactam doses studied ranged from 125-62.5 to 1,500-750 mg. Negative- and positive-control arms included no treatment and piperacillin-tazobactam at 4.5 g every 6 h, respectively. An inverted-U-shaped function best described the relationship between bacterial drug resistance amplification and drug exposure. The least- and most-intensive ceftolozane-tazobactam dosing regimens, i.e., 125-62.5, 750-375, 1,000-500, and 1,500-750 mg, did not amplify drug resistance, while drug resistance amplification was observed with intermediate-intensity dosing regimens (250-125 and 500-250 mg). For the intermediate-intensity ceftolozane-tazobactam dosing regimens, the drug-resistant subpopulation became the dominant population by days 4 to 6. The more-intensive ceftolozane-tazobactam dosing regimens (750-375, 1,000-500, and 1,500-750 mg) not only prevented drug resistance amplification but also virtually sterilized the model system. These data support the selection of ceftolozane-tazobactam dosing regimens that minimize the potential for on-therapy drug resistance amplification.

scholarly journals Relationship between Ceftolozane-Tazobactam Exposure and Selection for Pseudomonas aeruginosa Resistance in a Hollow-Fiber Infection Model

2014 ◽  
Vol 58 (10) ◽  
pp. 6024-6031 ◽  
Author(s):  
Brian D. VanScoy ◽  
Rodrigo E. Mendes ◽  
Mariana Castanheira ◽  
Jennifer McCauley ◽  
Sujata M. Bhavnani ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Infection Model ◽  
Drug Resistant ◽  
Wild Type ◽  
Resistance Selection ◽  
Atcc Strain ◽  
Dosing Regimens ◽  
Selection For ◽  
The Relationship ◽  
Selection Of

ABSTRACTIt is important to understand the relationship between antibiotic exposure and the selection of drug resistance in the context of therapy exposure. We sought to identify the ceftolozane-tazobactam exposure necessary to prevent the amplification of drug-resistant bacterial subpopulations in a hollow-fiber infection model. TwoPseudomonas aeruginosachallenge isolates were selected for study, a wild-type ATCC strain (ceftolozane-tazobactam MIC, 0.5 mg/liter) and a clinical isolate (ceftolozane-tazobactam MIC, 4 mg/liter). The experiment duration was 10 days, and the ceftolozane-tazobactam dose ratio (2:1) and dosing interval (every 8 h) were selected to approximate those expected to be used clinically. The studied ceftolozane-tazobactam dosing regimens ranged from 62.5/31.25 to 2,000/1,000 mg per dose in step fold dilutions. Negative-control arms included no treatment and tazobactam at 500 mg every 8 h. Positive-control arms included ceftolozane at 1 g every 8 h and piperacillin-tazobactam dosed at 4.5 g every 6 h. For the wild-type ATCC strain, resistance was not selected by any ceftolozane-tazobactam regimen evaluated. For the clinical isolate, an inverted-U-shaped function best described the relationship between the amplification of a drug-resistant subpopulation and drug exposure. The least (62.5/31.25 mg) and most (2,000/1,000 mg) intensive ceftolozane-tazobactam dosing regimens did not select for drug resistance. Drug resistance selection was observed with intermediately intensive dosing regimens (125/62.5 through 1,000/500 mg). For the intermediately intensive ceftolozane-tazobactam dosing regimens, the duration until the selection for drug resistance increased with dose regimen intensity. These data support the selection of ceftolozane-tazobactam dosing regimens that minimize the potential for on-therapy drug resistance selection.

scholarly journals Screening of anti-mycobacterial compounds in a naturally infected zebrafish embryo model

2016 ◽  
Author(s):  
James P Dalton ◽  
Benedict Uy ◽  
Kazuhide Okuda ◽  
Christopher J Hall ◽  
William A Denny ◽  
...  
Keyword(s):  
Zebrafish Embryo ◽  
Natural Infection ◽  
Rapid Screening ◽  
Infection Model ◽  
Zebrafish Embryos ◽  
Drug Trials ◽  
Bioluminescent Signal ◽  
High Level ◽  
Selection Of

Mycobacterium tuberculosisis a deadly human pathogen that latently infects a third of the worlds population, resulting in approximately 1.5 million deaths per year. Due to the difficulties and expense of carrying out animal drug trials using M. tuberculosis and rodents, infections of the zebrafishDanio reriowithM. marinumhave been used as a surrogate. However the methods so far described require specialised equipment and a high level of operator expertise. We investigated a natural infection model where zebrafish embryos are infected through incubation in media containingM. marinum. Using bioluminescently labelledM. marinum, we have characterised the nature of infection and established a model for interventional drug therapy. We have used a selection of traditional and experimental compounds to validate this model for anti-mycobacterial drug discovery. We observed that only three of the six treatments tested (Delamonid, SN30527 and rifampicin) retarded the growth ofM. marinumin vitro. In contrast, five of the six treatments (Pretomanid, Delamanid, SN30488, SN30527 and rifampicin) retarded the growth ofM. tuberculosisin vitro. Importantly, these same five treatments significantly reduced the bioluminescent signal from naturally infected zebrafish embryos. Overall this study has demonstrated that zebrafish embryos naturally infected with bioluminescentM. marinumM can be used for the rapid screening of anti-mycobacterial compounds with readily available equipment and limited expertise. The result is an assay that can be carried out by a wide variety of laboratories for minimal cost and without high levels of zebrafish expertise.

scholarly journals Our Exciting Journey to ACT-451840

2021 ◽  
Vol 75 (11) ◽  
pp. 916-922
Author(s):  
Christoph Boss ◽  
Sergio Wittlin
Keyword(s):  
Mouse Model ◽  
Mode Of Action ◽  
Antimalarial Drug ◽  
Malaria Infection ◽  
Infection Model ◽  
Therapeutic Effects ◽  
Oral Doses ◽  
Selection Of

We describe our work resulting in the selection of ACT-451840 ( 38 ) as a novel antimalarial drug with a novel mode of action. The compound was broadly characterized in vitro as well as in vivo in rat PK experiments as well as two different mouse malaria models. In the P. berghei infected mouse model cure could be achieved at oral doses of 300 mg/kg over 3 consecutive days. ACT-451840 was clinically investigated up to an experimental human malaria infection model, where therapeutic effects could be shown.

Clone selection of in vitro horseradish hairy root cultures

Planta Medica ◽  
2015 ◽  
Vol 81 (16) ◽  
Author(s):  
R Bertóti ◽  
Á Alberti ◽  
A Böszörményi ◽  
R Könye ◽  
T Horváth ◽  
...  
Keyword(s):  
Hairy Root ◽  
Hairy Root Cultures ◽  
Root Cultures ◽  
Clone Selection ◽  
Selection Of
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