Combination of polymyxin B and minocycline against multidrug-resistant Klebsiella pneumoniae: interaction quantified by pharmacokinetic/pharmacodynamic modelling from in vitro data

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.

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Emerging ceftazidime-avibactam resistance against carbapenem resistant Escherichia coli and Klebsiella pneumoniae in Lebanon

The International Arabic Journal of Antimicrobial Agents ◽

10.3823/858 ◽

2021 ◽

Author(s):

Ghena M Sobh ◽

Abdul Karim El Karaaoui ◽

Mira El Chaar ◽

George F Araj

Keyword(s):

Escherichia Coli ◽

Klebsiella Pneumoniae ◽

Carbapenem Resistant ◽

Novel Drug ◽

Vitro Data ◽

In Vitro Data ◽

Carbapenem Resistant Enterobacteriaceae

Ceftazidime-avibactam (CZA) has been introduced as a novel drug to essentially combat the rising trends of carbapenem resistant Enterobacteriaceae. In the absence of in vitro data about the activity of this drug against carbapenem resistant (CR) Escherichia coli and Klebsiella pneumoniae in Lebanon, this study was warranted.

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In Vitro Double and Triple Bactericidal Activities of Doripenem, Polymyxin B, and Rifampin against Multidrug-Resistant Acinetobacter baumannii, Pseudomonas aeruginosa, Klebsiella pneumoniae, and Escherichia coli

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.01768-09 ◽

2010 ◽

Vol 54 (6) ◽

pp. 2732-2734 ◽

Cited By ~ 61

Author(s):

Carl Urban ◽

Noriel Mariano ◽

James J. Rahal

Keyword(s):

Escherichia Coli ◽

Pseudomonas Aeruginosa ◽

Klebsiella Pneumoniae ◽

Acinetobacter Baumannii ◽

Carbapenem Resistance ◽

Polymyxin B ◽

Multidrug Resistant ◽

Carbapenem Resistant ◽

Bactericidal Activities

ABSTRACT In vitro double and triple bactericidal activities of doripenem, polymyxin B, and rifampin were assessed against 20 carbapenem-resistant clinical isolates with different mechanisms of carbapenem resistance. Bactericidal activity was achieved in 90% of all bacteria assayed using combinations of polymyxin B, doripenem, and rifampin against five each of the carbapenem-resistant Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Escherichia coli isolates studied. Combinations with these antibacterials may provide a strategy for treatment of patients infected with such organisms.

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Resveratrol enhances the antimicrobial effect of polymyxin B on Klebsiella pneumoniae and Escherichia coli isolates with polymyxin B resistance

BMC Microbiology ◽

10.1186/s12866-020-01995-1 ◽

2020 ◽

Vol 20 (1) ◽

Author(s):

Li Liu ◽

Jingyi Yu ◽

Xiaofei Shen ◽

Xingwei Cao ◽

Qing Zhan ◽

...

Keyword(s):

Escherichia Coli ◽

Klebsiella Pneumoniae ◽

Bacterial Infections ◽

Antimicrobial Effect ◽

Polymyxin B ◽

Multidrug Resistant ◽

Bacterial Strains ◽

Gram Negative ◽

Optimal Drug

Abstract Background Multidrug resistant (MDR) Gram-negative bacterial infections are a serious threat to human health due to the lack of effective treatments. In this study, we selected 50 Gram-negative bacterial strains, including 26 strains of Klebsiella pneumoniae and 24 strains of Escherichia coli, to explore whether resveratrol and polymyxin B have a synergistic killing effect. Results MIC values against polymyxin B were ≥ 4 μg/mL for 44 of the strains and were 2 μg/mL for the other 6 strains. MICs against polymyxin B in the isolates tested were significantly reduced by the addition of resveratrol. The degree of decline depended on the bacteria, ranging from 1/2 MIC to 1/512 MIC, and the higher the concentration of resveratrol, the greater the decrease. Checkerboard analysis indicated a synergistic effect between resveratrol and polymyxin B; the optimal drug concentration for different bacteria was different, that of resveratrol ranging from 32 μg/mL to 128 μg/mL. Subsequent time-kill experiments showed that a combination of polymyxin B and resveratrol was more effective in killing bacteria. Conclusions Our in vitro studies have shown that resveratrol can increase the sensitivity of MDR bacterial strains to polymyxin B, suggesting a potential new approach to the treatment of MDR infections.

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In Vitro Data Reveals Potential Novel Mechanism of Action of Teriflunomide on CNS Microglia and Astrocytes

10.26226/morressier.59a3eda8d462b8028d8951bb ◽

2017 ◽

Author(s):

Andrea Edling

Keyword(s):

Mechanism Of Action ◽

Vitro Data ◽

In Vitro Data

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Faculty Opinions recommendation of Carbapenemase-producing Klebsiella pneumoniae in Brooklyn, NY: molecular epidemiology and in vitro activity of polymyxin B and other agents.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1032764.374454 ◽

2006 ◽

Author(s):

Kenneth Thomson

Keyword(s):

Klebsiella Pneumoniae ◽

Molecular Epidemiology ◽

Polymyxin B ◽

Vitro Activity ◽

In Vitro Activity

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Faculty Opinions recommendation of Simulation and prediction of in vivo drug metabolism in human populations from in vitro data.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1091007.544382 ◽

2007 ◽

Author(s):

Marival Bermejo

Keyword(s):

Drug Metabolism ◽

Human Populations ◽

In Vivo Drug Metabolism ◽

Vitro Data ◽

In Vitro Data

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Use of Toxicokinetics in Risk Assessment Based on In Vitro Data

Alternatives to Laboratory Animals ◽

10.1177/026119299302100209 ◽

1993 ◽

Vol 21 (2) ◽

pp. 173-180

Author(s):

Gunnar Johanson

Keyword(s):

Risk Assessment ◽

Whole Body ◽

External Exposure ◽

Target Dose ◽

Toxic Response ◽

Route Of Exposure ◽

Vitro Data ◽

In Vitro Data

This presentation addresses some aspects of the methodology, advantages and problems associated with toxicokinetic modelling based on in vitro data. By using toxicokinetic models, particularly physiologically-based ones, it is possible, in principle, to describe whole body toxicokinetics, target doses and toxic effects from in vitro data. Modelling can be divided into three major steps: 1) to relate external exposure (applied dose) of xenobiotic to target dose; 2) to establish the relationship between target dose and effect (in vitro data, e.g. metabolism in microsomes, partitioning in tissue homogenates, and toxicity in cell cultures, are useful in both steps); and 3) to relate external exposure to toxic effect by combining the first two steps. Extrapolations from in vitro to in vivo, between animal and man, and between high and low doses, can easily be carried out by toxicokinetic simulations. In addition, several factors that may affect the toxic response by changing the target dose, such as route of exposure and physical activity, can be studied. New insights concerning the processes involved in toxicity often emerge during the design, refinement and validation of the model. The modelling approach is illustrated by two examples: 1) the carcinogenicity of 1,3-butadiene; and 2) the haematotoxicity of 2-butoxyethanol. Toxicokinetic modelling is an important tool in toxicological risk assessment based on in vitro data. Many factors, some of which can, and should be, studied in vitro, are involved in the expression of toxicity. Successful modelling depends on the identification and quantification of these factors.

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Lymphocutaneous spread of Mycobacterium elephantis in an immunocompetent individual: A case report

SAGE Open Medical Case Reports ◽

10.1177/2050313x211034913 ◽

2021 ◽

Vol 9 ◽

pp. 2050313X2110349

Author(s):

Brett D Edwards ◽

Ranjani Somayaji ◽

Dina Fisher ◽

Justin C Chia

Keyword(s):

Case Report ◽

Chronic Lung Disease ◽

Contaminated Soil ◽

Lung Abscess ◽

Immunocompetent Individual ◽

First Case ◽

Antimycobacterial Agents ◽

Vitro Data ◽

In Vitro Data

Mycobacterium elephantis was first described when isolated from an elephant that succumbed to lung abscess. However, despite this namesake, it is not associated with animals and has been described most often as a probable colonizer rather than pathogen in humans with chronic lung disease. In this report, we describe the first case of lymphocutaneous infection from M. elephantis, likely as a result of cutaneous inoculation with contaminated soil. This offers further evidence to its capabilities as a pathogen. We provide a review of the limited prior reports of M. elephantis and outline the available in vitro data on efficacy of various antimycobacterial agents.

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