scholarly journals Antagonism between Bacteriostatic and Bactericidal Antibiotics Is Prevalent

2014 ◽  
Vol 58 (8) ◽  
pp. 4573-4582 ◽  
Author(s):  
Paolo S. Ocampo ◽  
Viktória Lázár ◽  
Balázs Papp ◽  
Markus Arnoldini ◽  
Pia Abel zur Wiesch ◽  
...  
Keyword(s):  
Combination Therapy ◽  
Bacterial Infections ◽  
Time Lapse ◽  
Cellular Responses ◽  
Inhibition Of Growth ◽  
Drug Classes ◽  
Dividing Cells ◽  
Evolution Of Resistance ◽  
Time Kill ◽  
Antagonistic Interactions

ABSTRACTCombination therapy is rarely used to counter the evolution of resistance in bacterial infections. Expansion of the use of combination therapy requires knowledge of how drugs interact at inhibitory concentrations. More than 50 years ago, it was noted that, if bactericidal drugs are most potent with actively dividing cells, then the inhibition of growth induced by a bacteriostatic drug should result in an overall reduction of efficacy when the drug is used in combination with a bactericidal drug. Our goal here was to investigate this hypothesis systematically. We first constructed time-kill curves using five different antibiotics at clinically relevant concentrations, and we observed antagonism between bactericidal and bacteriostatic drugs. We extended our investigation by performing a screen of pairwise combinations of 21 different antibiotics at subinhibitory concentrations, and we found that strong antagonistic interactions were enriched significantly among combinations of bacteriostatic and bactericidal drugs. Finally, since our hypothesis relies on phenotypic effects produced by different drug classes, we recreated these experiments in a microfluidic device and performed time-lapse microscopy to directly observe and quantify the growth and division of individual cells with controlled antibiotic concentrations. While our single-cell observations supported the antagonism between bacteriostatic and bactericidal drugs, they revealed an unexpected variety of cellular responses to antagonistic drug combinations, suggesting that multiple mechanisms underlie the interactions.

scholarly journals Investigating the impact of combination phage and antibiotic therapy: a modeling study

2020 ◽  
Author(s):  
Selenne Banuelos ◽  
Hayriye Gulbudak ◽  
Mary Ann Horn ◽  
Qimin Huang ◽  
Aadrita Nandi ◽  
...  
Keyword(s):  
Immune System ◽  
Combination Therapy ◽  
Bacterial Infections ◽  
Phage Therapy ◽  
Antibiotic Use ◽  
Host Immune System ◽  
Drug Classes ◽  
The Impact ◽  
Antibiotic Combination

AbstractAntimicrobial resistance (AMR) is a serious threat to global health today. The spread of AMR, along with the lack of new drug classes in the antibiotic pipeline, has resulted in a renewed interest in phage therapy, which is the use of bacteriophages to treat pathogenic bacterial infections. This therapy, which was successfully used to treat a variety of infections in the early twentieth century, had been largely dismissed due to the discovery of easy to use antibiotics. However, the continuing emergence of antibiotic resistance has motivated new interest in the use of phage therapy to treat bacterial infections. Though various models have been developed to address the AMR-related issues, there are very few studies that consider the effect of phage-antibiotic combination therapy. Moreover, some of biological details such as the effect of the immune system on phage have been neglected. To address these limitations, we utilized a mathematical model to examine the role of the immune response in concert with phage-antibiotic combination therapy compounded with the effects of the immune system on the phages being used for treatment. We explore the effect of phage-antibiotic combination therapy by adjusting the phage and antibiotics dose or altering the timing. The model results show that it is important to consider the host immune system in the model and that frequency and dose of treatment are important considerations for the effectiveness of treatment. Our study can lead to development of optimal antibiotic use and further reduce the health risks of the human-animal-plant-ecosystem interface caused by AMR.

scholarly journals Surface Responses in Cultured Fibroblasts Elicited by Ethylenediaminetetraacetic Acid

1958 ◽  
Vol 4 (3) ◽  
pp. 243-250 ◽  
Author(s):  
Ernst J. Dornfeld ◽  
Alfred Owczarzak
Keyword(s):  
Ethylenediaminetetraacetic Acid ◽  
Divalent Cations ◽  
Chelating Agent ◽  
Time Lapse ◽  
Cellular Responses ◽  
Cultured Fibroblasts ◽  
Surface Activities ◽  
Dividing Cells ◽  
Chick Heart ◽  
And Migration

Cultures of chick heart fibroblasts were perfused with the chelating agent ethylenediaminetetraacetic acid (EDTA). Cellular responses were observed under phase optics and recorded by time-lapse cinemicrography. In interphasic fibroblasts, EDTA induces cellular contraction followed by continuous protrusion and retraction of ectoplasmic blebs ("surface bubbling"), formation of motile vermiform processes, and production of rotatory ectoplasmic swellings. The contraction and surface bubbling closely resemble the metaphase contraction and "anaphase bubbling" normally displayed by cultured fibroblasts. In dividing cells, EDTA does not affect metaphases, but anaphase bubbling appears and persists; telophasic expansion and migration of daughter cells are prevented. Initiation of new mitoses occurs during and after exposure to EDTA. No cellular responses are induced by calcium, magnesium, or ferrous chelates of EDTA. The EDTA elects are completely reversible on removal of the chelating agent, resulting in the restoration of the normal interphasic cell form and the normal expansion and migration of mitotic products. The EDTA effects are interpreted to result from the chelation and removal of divalent cations from the cell surface. Possible relations to surface activities observed in normal mitosis are considered, and an hypothesis is presented regarding the role of the developing spindle in cation transfer.

Emergence of ceftazidime/avibactam resistance in KPC-3-producing Klebsiella pneumoniae in vivo

2019 ◽  
Vol 74 (11) ◽  
pp. 3211-3216 ◽  
Author(s):  
Stephan Göttig ◽  
Denia Frank ◽  
Eleonora Mungo ◽  
Anika Nolte ◽  
Michael Hogardt ◽  
...  
Keyword(s):  
Combination Therapy ◽  
Klebsiella Pneumoniae ◽  
Selection Pressure ◽  
Galleria Mellonella ◽  
Phenotypic Characterization ◽  
Infection Model ◽  
Development Of Resistance ◽  
Time Kill

Abstract Objectives The β-lactam/β-lactamase inhibitor combination ceftazidime/avibactam is active against KPC-producing Enterobacterales. Herein, we present molecular and phenotypic characterization of ceftazidime/avibactam resistance in KPC-3-producing Klebsiella pneumoniae that emerged in vivo and in vitro. Methods Sequence analysis of blaKPC-3 was performed from clinical and in vitro-generated ceftazidime/avibactam-resistant K. pneumoniae isolates. Time–kill kinetics and the Galleria mellonella infection model were applied to evaluate the activity of ceftazidime/avibactam and imipenem alone and in combination. Results The ceftazidime/avibactam-resistant clinical K. pneumoniae isolate revealed the amino acid change D179Y in KPC-3. Sixteen novel mutational changes in KPC-3 among in vitro-selected ceftazidime/avibactam-resistant isolates were described. Time–kill kinetics showed the emergence of a resistant subpopulation under selection pressure with either imipenem or ceftazidime/avibactam. However, combined selection pressure with imipenem plus ceftazidime/avibactam prevented the development of resistance and resulted in bactericidal activity. Concordantly, the G. mellonella infection model revealed that monotherapy with ceftazidime/avibactam is prone to select for resistance in vivo and that combination therapy with imipenem results in significantly better survival. Conclusions Ceftazidime/avibactam is a valuable antibiotic against MDR and carbapenem-resistant Enterobacterales. Based on time–kill kinetics as well as an in vivo infection model we postulate a combination therapy of ceftazidime/avibactam and imipenem as a strategy to prevent the development of ceftazidime/avibactam resistance in KPC-producing Enterobacterales in vivo.

scholarly journals In Vitro Synergy and In Vivo Activity of Tigecycline-Ciprofloxacin Combination Therapy against Vibrio vulnificus Sepsis

2019 ◽  
Vol 63 (10) ◽  
Author(s):  
Seong Eun Kim ◽  
Hee Kyung Kim ◽  
Su-Mi Choi ◽  
Yohan Yu ◽  
Uh Jin Kim ◽  
...  
Keyword(s):  
Survival Rate ◽  
Mortality Rate ◽  
Combination Therapy ◽  
Combination Treatment ◽  
Vibrio Vulnificus ◽  
Antibiotic Regimen ◽  
Content Type ◽  
Time Kill

ABSTRACT The mortality rate associated with Vibrio vulnificus sepsis remains high. An in vitro time-kill assay revealed synergism between tigecycline and ciprofloxacin. The survival rate was significantly higher in mice treated with tigecycline plus ciprofloxacin than in mice treated with cefotaxime plus minocycline. Thus, combination treatment with tigecycline-ciprofloxacin may be an effective novel antibiotic regimen for V. vulnificus sepsis.

scholarly journals Cytokinesis and Midzone Microtubule Organization inCaenorhabditis elegans Require the Kinesin-like Protein ZEN-4

1998 ◽  
Vol 9 (8) ◽  
pp. 2037-2049 ◽  
Author(s):  
William B. Raich ◽  
Adrienne N. Moran ◽  
Joel H. Rothman ◽  
Jeff Hardin
Keyword(s):  
Cell Division ◽  
Null Allele ◽  
Time Lapse ◽  
Equatorial Region ◽  
Microtubule Organization ◽  
Dividing Cells ◽  
Spindle Midzone ◽  
Cross Links ◽  
Complete Cell

Members of the MKLP1 subfamily of kinesin motor proteins localize to the equatorial region of the spindle midzone and are capable of bundling antiparallel microtubules in vitro. Despite these intriguing characteristics, it is unclear what role these kinesins play in dividing cells, particularly within the context of a developing embryo. Here, we report the identification of a null allele ofzen-4, an MKLP1 homologue in the nematodeCaenorhabditis elegans, and demonstrate that ZEN-4 is essential for cytokinesis. Embryos deprived of ZEN-4 form multinucleate single-celled embryos as they continue to cycle through mitosis but fail to complete cell division. Initiation of the cytokinetic furrow occurs at the normal time and place, but furrow propagation halts prematurely. Time-lapse recordings and microtubule staining reveal that the cytokinesis defect is preceded by the dissociation of the midzone microtubules. We show that ZEN-4 protein localizes to the spindle midzone during anaphase and persists at the midbody region throughout cytokinesis. We propose that ZEN-4 directly cross-links the midzone microtubules and suggest that these microtubules are required for the completion of cytokinesis.

scholarly journals EFFECT OF THE HEXANIC EXTRACT OF TAGETES LUCIDA ON THE INHIBITION OF THE GROWTH OF ENTEROBACTERIA SHIGELLA FLEXNERI AND SALMONELLA TYPHI

2020 ◽  
pp. 113-116
Author(s):  
Jorge Ángel Almeida-Villegas ◽  
Rodolfo García-Contreras ◽  
Miriam Deyanira Rodríguez ◽  
Yahira Katherine Porras-Hernández ◽  
Meliksetyan Lilit Surenovna ◽  
...  
Keyword(s):  
Bacterial Infections ◽  
Shigella Flexneri ◽  
Salmonella Typhi ◽  
Hexane Extract ◽  
Gram Negative Bacteria ◽  
Active Metabolites ◽  
Inhibition Of Growth ◽  
Total Inhibition ◽  
Medicinal Plant Extracts ◽  
New Strategies

Antibiotic resistance increases the search for new strategies to combat the diseases they cause, and the use of medicinal plants represents a highly effective and valuable strategy, such as the use of Tagetes lucida with different gram positive and gram negative bacteria. Objective: To evaluate the biological activity of the hexane extract of the Tagetes lucida plant at different concentrations on the inhibition of growth in plaque and tube of two enterobacteriaceae, Shigella flexneri and Salmonella typhi Methods: In the following work, a hexane extract from Tagetes lucida was evaluated on the growth inhibition of two enterobacteriaceae, Shigella flexneri and Salmonella typhi using different concentrations of vehicle to evaluate if it affected bacterial growth and also different concentrations of extract to evaluate activity. Results: Once the studies were carried out in triplicate, it was possible to specify that from 75µl/µg of extract, almost total inhibition of the growth of both bacteria was achieved, both in the plate method and in the tube method. And from 100 µl/µg total inhibition is achieved. Conclusions: The favorable results obtained with 75 µl/ µg, confirm that medicinal plant extracts are an important strategy to combat multi-drug resistant bacterial infections. On the other hand, it allows a study to be carried out to evaluate the most active metabolites of the extract, as well as the mechanism of action on the inhibition of the growth of the bacteria under study.

scholarly journals Changes in the Min Oscillation Pattern before and after Cell Birth

2010 ◽  
Vol 192 (16) ◽  
pp. 4134-4142 ◽  
Author(s):  
Jennifer R. Juarez ◽  
William Margolin
Keyword(s):  
Cell Division ◽  
Fluorescent Protein ◽  
Time Lapse ◽  
The Other ◽  
Cell Pole ◽  
Daughter Cells ◽  
Division Site ◽  
Before And After ◽  
Dividing Cells ◽  
Green Fluorescent

ABSTRACT The Min system regulates the positioning of the cell division site in many bacteria. In Escherichia coli, MinD migrates rapidly from one cell pole to the other. In conjunction with MinC, MinD helps to prevent unwanted FtsZ rings from assembling at the poles and to stabilize their positioning at midcell. Using time-lapse microscopy of growing and dividing cells expressing a gfp-minD fusion, we show that green fluorescent protein (GFP)-MinD often paused at midcell in addition to at the poles, and the frequency of midcell pausing increased as cells grew longer and cell division approached. At later stages of septum formation, GFP-MinD often paused specifically on only one side of the septum, followed by migration to the other side of the septum or to a cell pole. About the time of septum closure, this irregular pattern often switched to a transient double pole-to-pole oscillation in the daughter cells, which ultimately became a stable double oscillation. The splitting of a single MinD zone into two depends on the developing septum and is a potential mechanism to explain how MinD is distributed equitably to both daughter cells. Septal pausing of GFP-MinD did not require MinC, suggesting that MinC-FtsZ interactions do not drive MinD-septal interactions, and instead MinD recognizes a specific geometric, lipid, and/or protein target at the developing septum. Finally, we observed regular end-to-end oscillation over very short distances along the long axes of minicells, supporting the importance of geometry in MinD localization.

Regulation of Mitosis

1969 ◽  
Vol 5 (3) ◽  
pp. 745-755
Author(s):  
W. T. JACKSON
Keyword(s):  
Mitotic Spindle ◽  
Time Lapse ◽  
Polarization Microscopy ◽  
Animal Cells ◽  
Higher Plant ◽  
Competitive Antagonism ◽  
Dividing Cells ◽  
Spindle Microtubules ◽  
Giant Nuclei

Earlier studies on the effects of the herbicide isopropyl N-phenylcarbamate (IPC) on mitosis revealed blocked metaphases, multinucleate cells, giant nuclei and an increase in number of partly contracted chromosomes. It was assumed that IPC, like colchicine, was causing these effects by disruption of the spindle apparatus by destroying the spindle microtubules. The animal hormone melatonin causes an increase in birefringence of the mitotic spindle in animal cells, presumably by increasing the number of microtubules. We have studied the effects of IPC, melatonin, and combinations of the two on mitosis in dividing endosperm cells of the African blood lily (Haemanthus katherinae Baker) in vivo by phase-contrast and polarization microscopy. Both qualitative and quantitative data are presented. Interpretation of these results has been aided materially by a time-lapse cinemicrographic analysis of dividing cells subjected to 1 and 10 p.p.m. IPC (unpublished) and by an accompanying fine-structural analysis of untreated and IPC-treated cells. Mitosis was disrupted by 0.01-10 p.p.m. IPC, the severity of the effect depending on both concentration and stage of mitosis of the cell at the time of treatment. Concentrations of IPC that caused cessation of chromosome movement also caused loss of birefringence of the mitotic spindle. Melatonin increased birefringence of the mitotic spindle in these plant cells and partly nullified the adverse effects of IPC. The results of this study demonstrate that the herbicide IPC, under our conditions, causes disruption of mitosis and loss of birefringence of the spindle. And it has been established that an animal hormone is capable of increasing the birefringence, and presumably the number of microtubules, of the mitotic spindle in dividing endosperm cells of a higher plant. Although melatonin is capable of partly nullifying the effects of IPC, a competitive antagonism is not postulated.

scholarly journals Efficacy of Antibiotic Combinations against Multidrug-Resistant Pseudomonas aeruginosa in Automated Time-Lapse Microscopy and Static Time-Kill Experiments

2020 ◽  
Vol 64 (6) ◽  
Author(s):  
Anna Olsson ◽  
Pikkei Wistrand-Yuen ◽  
Elisabet I. Nielsen ◽  
Lena E. Friberg ◽  
Linus Sandegren ◽  
...  
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Time Lapse ◽  
Polymyxin B ◽  
Multidrug Resistant ◽  
Positive Interactions ◽  
Synergistic Activity ◽  
Content Type ◽  
Time Lapse Microscopy ◽  
Time Kill ◽  
Antibiotic Combination

ABSTRACT Antibiotic combination therapy is used for severe infections caused by multidrug-resistant (MDR) Gram-negative bacteria, yet data regarding which combinations are most effective are lacking. This study aimed to evaluate the in vitro efficacy of polymyxin B in combination with 13 other antibiotics against four clinical strains of MDR Pseudomonas aeruginosa. We evaluated the interactions of polymyxin B in combination with amikacin, aztreonam, cefepime, chloramphenicol, ciprofloxacin, fosfomycin, linezolid, meropenem, minocycline, rifampin, temocillin, thiamphenicol, or trimethoprim by automated time-lapse microscopy using predefined cutoff values indicating inhibition of growth (≤106 CFU/ml) at 24 h. Promising combinations were subsequently evaluated in static time-kill experiments. All strains were intermediate or resistant to polymyxin B, antipseudomonal β-lactams, ciprofloxacin, and amikacin. Genes encoding β-lactamases (e.g., blaPAO and blaOXA-50) and mutations associated with permeability and efflux were detected in all strains. In the time-lapse microscopy experiments, positive interactions were found with 39 of 52 antibiotic combination/bacterial strain setups. Enhanced activity was found against all four strains with polymyxin B used in combination with aztreonam, cefepime, fosfomycin, minocycline, thiamphenicol, and trimethoprim. Time-kill experiments showed additive or synergistic activity with 27 of the 39 tested polymyxin B combinations, most frequently with aztreonam, cefepime, and meropenem. Positive interactions were frequently found with the tested combinations, against strains that harbored several resistance mechanisms to the single drugs, and with antibiotics that are normally not active against P. aeruginosa. Further study is needed to explore the clinical utility of these combinations.

scholarly journals Weakest-Link Dynamics Predict Apparent Antibiotic Interactions in a Model Cross-Feeding Community

2020 ◽  
Vol 64 (11) ◽  
Author(s):  
Elizabeth M. Adamowicz ◽  
William R. Harcombe
Keyword(s):  
Antimicrobial Resistance ◽  
Combination Therapy ◽  
Bacterial Infections ◽  
Interaction Patterns ◽  
Weakest Link ◽  
Infection Treatment ◽  
Additional Challenge ◽  
Global Threat ◽  
Multiple Drugs ◽  
Antibiotic Interactions

ABSTRACT With the growing global threat of antimicrobial resistance, novel strategies are required for combatting resistant pathogens. Combination therapy, in which multiple drugs are used to treat an infection, has proven highly successful in the treatment of cancer and HIV. However, this practice has proven challenging for the treatment of bacterial infections due to difficulties in selecting the correct combinations and dosages. An additional challenge in infection treatment is the polymicrobial nature of many infections, which may respond to antibiotics differently than a monoculture pathogen. This study tests whether patterns of antibiotic interactions (synergy, antagonism, or independence/additivity) in monoculture can be used to predict antibiotic interactions in an obligate cross-feeding coculture. Using our previously described weakest-link hypothesis, we hypothesized antibiotic interactions in coculture based on the interactions we observed in monoculture. We then compared our predictions to observed antibiotic interactions in coculture. We tested the interactions between 10 previously identified antibiotic combinations using checkerboard assays. Although our antibiotic combinations interacted differently than predicted in our monocultures, our monoculture results were generally sufficient to predict coculture patterns based solely on the weakest-link hypothesis. These results suggest that combination therapy for cross-feeding multispecies infections may be successfully designed based on antibiotic interaction patterns for their component species.

Sign in / Sign up

Export Citation Format

Share Document