scholarly journals Combining antibiotics with antivirulence compounds can have synergistic effects and reverse selection for antibiotic resistance in Pseudomonas aeruginosa

2019 ◽  
Author(s):  
Chiara Rezzoagli ◽  
Martina Archetti ◽  
Ingrid Mignot ◽  
Michael Baumgartner ◽  
Rolf Kümmerli
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Antibiotic Resistance ◽  
Synergistic Effects ◽  
Rapid Evolution ◽  
Resistance Mechanisms ◽  
Interaction Patterns ◽  
Systematic Analysis ◽  
Antibiotic Resistant ◽  
Drug Concentrations ◽  
Selection For

AbstractAntibiotics are losing efficacy due to the rapid evolution and spread of resistance. Treatments targeting bacterial virulence factors have been considered as alternatives because they target virulence instead of pathogen viability, and should therefore exert weaker selection for resistance than conventional antibiotics. However, antivirulence treatments rarely clear infections, which compromises their clinical applications. Here, we explore the potential of combining antivirulence drugs with antibiotics against the opportunistic human pathogen Pseudomonas aeruginosa. We combined two antivirulence compounds (gallium, a siderophore-quencher, and furanone C-30, a quorum sensing-inhibitor) together with four clinically relevant antibiotics (ciprofloxacin, colistin, meropenem, tobramycin) in 9×9 drug concentration matrices. We found that drug-interaction patterns were concentration dependent, with promising levels of synergies occurring at intermediate drug concentrations for certain drug pairs. We then tested whether antivirulence compounds are potent adjuvants, especially when treating antibiotic resistant clones. We found that the addition of antivirulence compounds to antibiotics could restore growth inhibition for most antibiotic resistant clones, and even abrogate or reverse selection for resistance in five drug combination cases. Molecular analyses suggest that selection against resistant clones occurs when resistance mechanisms involve restoration of protein synthesis, but not when efflux pumps are upregulated. Altogether, our work provides a first systematic analysis of antivirulence-antibiotic combinatorial treatments and suggests that such combinations have a high potential to be both effective in treating infections and in limiting the spread of antibiotic resistance.

scholarly journals Microbiological and Molecular Genetic Aspects of Antibiotic Resistance of Pseudomonas aeruginosa and Acinetobacter baumannii

2020 ◽  
Vol 18 (6) ◽  
pp. 34-38
Author(s):  
Yu. E. Skurikhina ◽  
V. B. Turkutyukov
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Antibiotic Resistance ◽  
Acinetobacter Baumannii ◽  
Molecular Genetic ◽  
Resistance Mechanisms ◽  
Steady Increase ◽  
Molecular Genetic Study ◽  
Antibiotic Resistant ◽  
Resistant Strains ◽  
High Level

Relevance. The increase in the frequency of infections caused by Pseudomonas aeruginosa and Acinetobacter baumannii, which have a high level of resistance to many groups of antibiotics, requires a comprehensive study, including modern research methods.Aims. The study of regional features of the dynamics of the formation and circulation of antibiotic-resistant strains A. baumannii and P. aeruginosa.Materials and methods. During 2009-2018 we analyzed the data of microbiological laboratories of multidisciplinary hospitals and carried out a molecular genetic study of the determinants of antibiotic resistance by PCR of A. baumannii and P. aeruginosa strains isolated from clinical material in order to determine the level of variability of resistance.Results. The study revealed a tendency to increase in the proportion of strains A. baumannii and P. aeruginosa in the etiological structure of healh-care associated infections and purulent-septic infections; high incidence of strains resistant to cephalosporins, carbapenems, beta-lactams and multi-resistant strains. The appearance and distribution of the determinants of antibiotic resistance NDM-1 and MCR-1 in these bacteria were also detected.Conclusions. Over the past decade, a steady increase in the proportion of A. baumannii and P. Aeruginosa resistant to many antibiotics in patients in intensive care unit and surgery departments in hospitals of Vladivostok (Primorsky reg., Russia), and the emergence of new antimicrobial resistance mechanisms in these microorganisms.

scholarly journals Combining antibiotics with antivirulence compounds can have synergistic effects and reverse selection for antibiotic resistance in Pseudomonas aeruginosa

PLoS Biology ◽  
2020 ◽  
Vol 18 (8) ◽  
pp. e3000805 ◽  
Author(s):  
Chiara Rezzoagli ◽  
Martina Archetti ◽  
Ingrid Mignot ◽  
Michael Baumgartner ◽  
Rolf Kümmerli
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Antibiotic Resistance ◽  
Synergistic Effects ◽  
Selection For

scholarly journals Evolution under low antibiotic concentrations: a risk for the selection of Pseudomonas aeruginosa multidrug resistant mutants in nature

2021 ◽  
Author(s):  
Fernando Sanz-García ◽  
Sara Hernando-Amado ◽  
José Luis Martínez
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Antibiotic Resistance ◽  
Polymyxin B ◽  
Multidrug Resistant ◽  
Resistant Bacteria ◽  
Published Data ◽  
Natural Ecosystems ◽  
Clinical Value ◽  
Drug Concentrations ◽  
Resistant Mutants

ABSTRACTBACKGROUNDAntibiotic pollution of non-clinical environments might have a relevant impact on human health if resistant pathogens are selected. However, this potential risk is often overlooked, since drug concentrations in nature are usually below their minimal inhibitory concentrations (MICs). Albeit, antibiotic resistant bacteria can be selected even at sub-MIC concentrations, in a range that is dubbed the sub-MIC selective window, which depends on both the antibiotic and the pathogen.OBJECTIVESDetermine the sub-MIC selective windows of seven antibiotics of clinical relevance in the opportunistic pathogen Pseudomonas aeruginosa and evaluate the risk for selecting resistant mutants in nature, based on published data about the amount of antimicrobials detected in natural environments.METHODSWe conducted evolution experiments of P. aeruginosa PA14 in presence of sub-MIC concentrations of ceftazidime, amikacin, levofloxacin, ciprofloxacin, tetracycline, polymyxin B or imipenem, and measured drug susceptibility of the evolved populations.RESULTSSub-MIC selective window of quinolones was the largest, and the ones of polymyxin B and imipenem, the narrowest. Clinically relevant multidrug resistant (MDR) mutants (presenting MICs above EUCAST clinical breakpoints) arose within the sub-MIC selective windows of the majority of antibiotics tested, being these phenotypes probably mediated by efflux pumps′ activity.DISCUSSIONOur data show that the concentration of antibiotics reported in aquatic ecosystems -colonizable by P. aeruginosa- are, in occasions, higher than the ones able to select MDR mutants. This finding has implications for understanding the role of different ecosystems and conditions in the emergence of antibiotic resistance from a One-Health point of view. Further, it highlights the importance of delineating the sub-MIC selective windows for drugs of clinical value in pathogens with environmental niches, in order to evaluate the health risks due to antibiotic pollution of natural ecosystems and ultimately tackle antibiotic resistance.

Comparative evaluation of Assays for Broad Detection of Molecular Resistance Mechanisms in Enterobacterales Isolates

2021 ◽  
Author(s):  
J. N. Brazelton de Cardenas ◽  
C. D. Garner ◽  
Y Su ◽  
L Tang ◽  
R. T. Hayden
Keyword(s):  
Antibiotic Resistance ◽  
Rapid Evolution ◽  
Antibiotic Resistance Genes ◽  
Resistance Mechanisms ◽  
Beta Lactam ◽  
Accurate Identification ◽  
Gram Negative ◽  
Diagnostic Role ◽  
Clinically Significant ◽  
Third Generation Cephalosporins

Rapid detection of antimicrobial resistance in both surveillance and diagnostic settings is still a major challenge for the clinical lab, compounded by the rapid evolution of antibiotic resistance mechanisms. This study compares four methods for the broad detection of antibiotic resistance genes in Enterobacterales isolates: two multiplex PCR assays, (the Streck ARM-D® beta-lactamase kit and the OpGen Acuitas AMR Gene Panel u5.47 (research use only (RUO)), and one microarray assay (the Check-MDR CT103XL assay), with whole genome sequencing as a reference standard. A total of 65 Gram-negative bacterial isolates, from 56 patients, classified by phenotypic AST as showing resistance to beta-lactam antimicrobials (ESBL positive, resistance to third generation cephalosporins or carbapenems), were included in the study. Overall concordance between the molecular assays and sequencing was high. While all three assays had similar performance, the OpGen Acuitas AMR assay had the highest overall percent concordance with sequencing results. The primary differences between the assays tested were the number and diversity of targets, ranging from 9 for Streck to 34 for OpGen. This study shows that commercially available PCR-based assays can provide accurate identification of antimicrobial resistant loci in clinically significant Gram-negative bacteria. Further studies are needed to determine the clinical diagnostic role and potential benefit of such methods.

scholarly journals Phage steering of antibiotic-resistance evolution in the bacterial pathogen, Pseudomonas aeruginosa

2020 ◽  
Vol 2020 (1) ◽  
pp. 148-157 ◽  
Author(s):  
James Gurney ◽  
Léa Pradier ◽  
Joanne S Griffin ◽  
Claire Gougat-Barbera ◽  
Benjamin K Chan ◽  
...  
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Antibiotic Resistance ◽  
Bacterial Pathogen ◽  
Antibiotic Sensitivity ◽  
Resistant Bacteria ◽  
Phage Resistance ◽  
Antibiotic Resistant ◽  
Trade Off

Abstract Background and objectives Antimicrobial resistance is a growing global concern and has spurred increasing efforts to find alternative therapeutics. Bacteriophage therapy has seen near constant use in Eastern Europe since its discovery over a century ago. One promising approach is to use phages that not only reduce bacterial pathogen loads but also select for phage resistance mechanisms that trade-off with antibiotic resistance—so called ‘phage steering’. Methodology Recent work has shown that the phage OMKO1 can interact with efflux pumps and in so doing select for both phage resistance and antibiotic sensitivity of the pathogenic bacterium Pseudomonas aeruginosa. We tested the robustness of this approach to three different antibiotics in vitro (tetracycline, erythromycin and ciprofloxacin) and one in vivo (erythromycin). Results We show that in vitro OMKO1 can reduce antibiotic resistance of P. aeruginosa (Washington PAO1) even in the presence of antibiotics, an effect still detectable after ca.70 bacterial generations in continuous culture with phage. Our in vivo experiment showed that phage both increased the survival times of wax moth larvae (Galleria mellonella) and increased bacterial sensitivity to erythromycin. This increased antibiotic sensitivity occurred both in lines with and without the antibiotic. Conclusions and implications Our study supports a trade-off between antibiotic resistance and phage sensitivity. This trade-off was maintained over co-evolutionary time scales even under combined phage and antibiotic pressure. Similarly, OMKO1 maintained this trade-off in vivo, again under dual phage/antibiotic pressure. Our findings have implications for the future clinical use of steering in phage therapies. Lay Summary: Given the rise of antibiotic-resistant bacterial infection, new approaches to treatment are urgently needed. Bacteriophages (phages) are bacterial viruses. The use of such viruses to treat infections has been in near-continuous use in several countries since the early 1900s. Recent developments have shown that these viruses are not only effective against routine infections but can also target antibiotic resistant bacteria in a novel, unexpected way. Similar to other lytic phages, these so-called ‘steering phages’ kill the majority of bacteria directly. However, steering phages also leave behind bacterial variants that resist the phages, but are now sensitive to antibiotics. Treatment combinations of these phages and antibiotics can now be used to greater effect than either one independently. We evaluated the impact of steering using phage OMKO1 and a panel of three antibiotics on Pseudomonas aeruginosa, an important pathogen in hospital settings and in people with cystic fibrosis. Our findings indicate that OMKO1, either alone or in combination with antibiotics, maintains antibiotic sensitivity both in vitro and in vivo, giving hope that phage steering will be an effective treatment option against antibiotic-resistant bacteria.

scholarly journals Comparison of the Activity of a Human Simulated, High-Dose, Prolonged Infusion of Meropenem against Klebsiella pneumoniae Producing the KPC Carbapenemase versus That against Pseudomonas aeruginosa in an In Vitro Pharmacodynamic Model

2009 ◽  
Vol 54 (2) ◽  
pp. 804-810 ◽  
Author(s):  
Catharine C. Bulik ◽  
Henry Christensen ◽  
Peng Li ◽  
Christina A. Sutherland ◽  
David P. Nicolau ◽  
...  
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Klebsiella Pneumoniae ◽  
High Performance ◽  
Resistance Mechanisms ◽  
Free Drug ◽  
Pharmacodynamic Model ◽  
High Dose ◽  
Prolonged Infusion ◽  
Drug Concentrations

ABSTRACT We have previously demonstrated that a high-dose, prolonged-infusion meropenem regimen (2 g every 8 h [q8h]; 3-hour infusion) can achieve 40% free drug concentration above the MIC against Pseudomonas aeruginosa with MICs of ≤16 μg/ml. The objective of this experiment was to compare the efficacy of this high-dose, prolonged-infusion regimen against carbapenemase-producing Klebsiella pneumoniae isolates with the efficacy against P. aeruginosa isolates having similar meropenem MICs. An in vitro pharmacodynamic model was used to simulate human serum concentrations. Eleven genotypically confirmed K. pneumoniae carbapenemase (KPC)-producing isolates and six clinical P. aeruginosa isolates were tested for 24 h, and time-kill curves were constructed. High-performance liquid chromatography (HPLC) was used to verify meropenem concentrations in each experiment. Meropenem achieved a rapid ≥3 log CFU reduction against all KPC isolates within 6 h, followed by regrowth in all but two isolates. The targeted %fT>MIC (percent time that free drug concentrations remain above the MIC) exposure was achieved against both of these KPC isolates (100% fT>MIC versus MIC = 2 μg/ml, 75% fT>MIC versus MIC = 8 μg/ml). Against KPC isolates with MICs of 8 and 16 μg/ml that did regrow, actual meropenem exposures were significantly lower than targeted due to rapid in vitro hydrolysis, whereby targeted %fT>MIC was reduced with each subsequent dosing. In contrast, a ≥3 log CFU reduction was maintained over 24 h for all Pseudomonas isolates with meropenem MICs of 8 and 16 μg/ml. Although KPC and P. aeruginosa isolates may share similar meropenem MICs, the differing resistance mechanisms produce discordant responses to a high-dose, prolonged infusion of meropenem. Thus, predicting the efficacy of an antimicrobial regimen based on MIC may not be a valid assumption for KPC-producing organisms.

scholarly journals Two resistance nodulation division-family efflux pumps inChromobacteriumspecies and their role in antibiotic resistance and tolerance

2019 ◽  
Author(s):  
Saida Benomar ◽  
Kara C Evans ◽  
Robert L Unckless ◽  
Josephine R Chandler
Keyword(s):  
Antibiotic Resistance ◽  
Efflux Pump ◽  
Bacterial Species ◽  
Efflux Pumps ◽  
Resistance Mechanisms ◽  
Antibiotic Resistant ◽  
Burkholderia Thailandensis ◽  
New Information ◽  
Resistance Nodulation Division ◽  
Culture Growth

ABSTRACTVery little is known of the antibiotic resistance mechanisms of members of theChromobacteriumgenus. In previous studies ofChromobacterium subtsugae(formerlyC. violaceum) strain CV017, we identified a resistance nodulation division (RND)-family efflux pump (CdeAB-OprM). Here, we show thecdeAB-oprMgenes are widely distributed in members of theChromobacteriumgenus. We use antimicrobial susceptibility testing with a CV017cdeAB-oprMmutant to show the products of these genes confers resistance to a variety of antibiotics including ciprofloxacin, a clinically important antibiotic. We also identified a related RND-family pump,cseAB-oprN, in the genome of CV017 and otherC. subtsugaespecies, that is not present in other members of theChromobacteriumgenus. We demonstrate that CdeAB-OprM and CseAB-OprN are both transcriptionally induced in CV017 cells treated with sub-lethal antibiotic concentrations and they are important for induction of tolerance to different antibiotics. While CdeAB-OprM has a broad antibiotic specificity, the CseAB-OprN system is highly specific for a ribosome-targeting antibiotic produced by the saprophytic bacteriumBurkholderia thailandensis,bactobolin. Finally, we use a previously developedB. thailandensis-C. subtsugaeCV017 co-culture model to demonstrate that adding sub-lethal bactobolin at the beginning of co-culture growth increases the ability of CV017 to compete withB. thailandensisin a manner that is dependent on the CseAB-OprN system. Our results provide new information on the antibiotic resistance mechanisms ofChromobacteriumspecies and highlight the importance of efflux pumps during competition with other bacterial species.IMPORTANCEThis study describes two closely related efflux pumps in members of theChromobacteriumgenus, which includes opportunistic but often-fatal pathogens and species with highly versatile metabolic capabilities. Efflux pumps remove antibiotics from the cell and are important for antibiotic resistance. One of these pumps is broadly distributed in theChromobacteriumgenus and increases resistance to clinically relevant antibiotics. The other efflux pump is present only inChromobacterium subtsugaeand is highly specific for bactobolin, an antibiotic produced by the soil saprophyteBurkholderia thailandensis. We demonstrate these pumps can be activated to increase resistance by their antibiotic substrates, and that this activation is important forC. subtsugaeto survive in a laboratory competition experiment withB. thailandensis.These results have implications for managing antibiotic-resistantChromobacteriuminfections, bioengineering ofChromobacteriumspecies, and for understanding the evolution of efflux pumps.

scholarly journals Role of biofilm-specific antibiotic resistance genes PA0756-0757, PA5033 and PA2070 in Pseudomonas aeruginosa

2018 ◽  
Author(s):  
Prasanth Manohar ◽  
Thamaraiselvan Shanthini ◽  
Reethu Ann Philip ◽  
Subramani Ramkumar ◽  
Manali Kale ◽  
...  
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Antibiotic Resistance ◽  
Resistance Genes ◽  
Biofilm Formation ◽  
Tamil Nadu ◽  
Antibiotic Resistance Genes ◽  
Clinical Samples ◽  
Cross Sectional ◽  
Antibiotic Resistant ◽  
Resistant Genes

AbstractTo evaluate the presence of biofilm-specific antibiotic-resistant genes, PA0756-0757, PA5033 and PA2070 in Pseudomonas aeruginosa isolated from clinical samples in Tamil Nadu. For this cross-sectional study, 24 clinical isolates (included pus, urine, wound, and blood) were collected from two diagnostic centers in Chennai from May 2015 to February 2016. Biofilm formation was assessed using microtiter dish biofilm formation assay and minimal inhibitory concentration (MIC) and minimal bactericidal concentrations (MBC) were determined for planktonic and biofilm cells (MBC assay). Further, PCR amplification of biofilm-specific antibiotic resistance genes PA0756-0757, PA5033 and PA2070 were performed. Biofilm formation was found to be moderate/strong in 16 strains. MBC for planktonic cells showed that 4, 7, 10 and 14 strains were susceptible to gentamicin, ciprofloxacin, meropenem and colistin respectively. In MBC assay for biofilm cells (MBC-B), all the 16 biofilm producing strains were resistant to ciprofloxacin and gentamicin whereas nine and four were resistant to meropenem, and colistin respectively. The biofilm-specific antibiotic-resistant genes PA0756-0757 was found in 10 strains, 6 strains with PA5033 and 9 strains with PA2070 that were found to be resistant phenotypically. This study highlighted the importance of biofilm-specific antibiotic resistance genes PA0756-0757, PA5033, and PA2070 in biofilm-forming P. aeruginosa.

scholarly journals ANTIBIOTIC RESISTANCE MECHANISMS OF UROGENITAL MYCOPLASMAS

2019 ◽  
pp. 45-49
Author(s):  
E.A. Kolesnikova ◽  
N.F. Brusnigina ◽  
G.I. Grigor’eva
Keyword(s):  
Antibiotic Resistance ◽  
Mycoplasma Hominis ◽  
Mycoplasma Genitalium ◽  
Resistance Mechanisms ◽  
Resistant Bacteria ◽  
Antibiotic Resistant ◽  
Resistance Determinants ◽  
New Knowledge ◽  
High Level ◽  
Ureaplasma Spp

Urogenital mycoplasmas (Mycoplasma genitalium, Mycoplasma hominis and Ureaplasma spp.) currently prevail in the etiology of infections of the urogenital tract and are characterized by a high level of genetic polymorphism responsible for the occurrence of their antibiotic resistance. The review presents the data of domestic and foreign researchers on the resistance mechanisms of mycoplasmas and ureaplasmas to antibiotics and considers the acquisition by mycoplasmas of antibiotic resistance determinants. New knowledge of resistance mechanisms is important theoretical basis for improving measures to limit and prevent the spread of antibiotic resistant bacteria.

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