scholarly journals The Effects of Sub-inhibitory Antibiotic Concentrations on Pseudomonas aeruginosa: Reduced Susceptibility Due to Mutations

2021 ◽  
Vol 12 ◽  
Author(s):  
Kay A. Ramsay ◽  
Sharla M. McTavish ◽  
Samuel J. T. Wardell ◽  
Iain L. Lamont
Keyword(s):  
Cystic Fibrosis ◽  
Pseudomonas Aeruginosa ◽  
Antibiotic Susceptibility ◽  
Resistant Bacteria ◽  
Antibiotic Exposure ◽  
Aminoglycoside Resistance ◽  
Antibiotic Resistant ◽  
Aminoglycoside Resistance Genes ◽  
Reference Strains ◽  
Antibiotic Resistant Mutants

Pseudomonas aeruginosa chronically infects in the lungs of people with cystic fibrosis and other forms of lung disease. Infections are treated with antibiotics, but over time, the bacteria acquire mutations that reduce their antibiotic susceptibility. The effects of inhibitory amounts of antibiotics in selecting for antibiotic-resistant mutants have been well studied. However, the concentrations of antibiotics that reach infecting bacteria can be sub-inhibitory and but may nonetheless promote emergence of antibiotic-resistant bacteria. Therefore, the aim of this research was to investigate the effects of sub-inhibitory concentrations of antibiotics on the antibiotic susceptibility of P. aeruginosa. Two P. aeruginosa reference strains, PAO1 and PA14, and six isolates from individuals with cystic fibrosis were studied. The bacteria were passaged in the presence of antibiotics (ceftazidime, ciprofloxacin, meropenem or tobramycin) at sub-inhibitory amounts. Fifteen populations of bacteria (up to five per strain) were exposed to each of the four antibiotics. Antibiotic susceptibility was determined following 10 passages on agar supplemented with antibiotic and compared with susceptibility prior to antibiotic exposure. Antibiotic exposure resulted in susceptibility being significantly (>2-fold) reduced for 13 of the 60 populations. Seven samples had reduced susceptibility to ciprofloxacin, three to tobramycin, two to ceftazidime and one to meropenem. Whole-genome sequencing revealed the mutations arising following antibiotic exposure. Mutants with reduced antibiotic susceptibility had mutations in genes known to affect antibiotic resistance, including regulators of efflux pumps (mexR, mexS, mexZ and nalC) and the fusA1 gene that is associated with aminoglycoside resistance. Genes not previously associated with resistance, including gacS, sigX and crfX and two genes with no known function, were also mutated in some isolates with reduced antibiotic susceptibility. Our results show that exposure to sub-inhibitory amounts of antibiotics can select for mutations that reduce the susceptibility of P. aeruginosa to antibiotics and that the profile of mutations is different from that arising during selection with inhibitory antibiotic concentrations. It is likely that exposure to sub-inhibitory amounts of antibiotics during infection contributes to P. aeruginosa becoming antibiotic-resistant.

scholarly journals Metabotypes of Pseudomonas aeruginosa Correlate with Antibiotic Resistance, Virulence and Clinical Outcome in Cystic Fibrosis Chronic Infections

Metabolites ◽  
2021 ◽  
Vol 11 (2) ◽  
pp. 63
Author(s):  
Oriane Moyne ◽  
Florence Castelli ◽  
Dominique J. Bicout ◽  
Julien Boccard ◽  
Boubou Camara ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Pseudomonas Aeruginosa ◽  
Antibiotic Resistance ◽  
Multiscale Analysis ◽  
Resistant Bacteria ◽  
Chronic Infections ◽  
Antibiotic Resistant ◽  
Causes Of Mortality ◽  
Lung Infections ◽  
Clinical Measurements

Pseudomonas aeruginosa (P.a) is one of the most critical antibiotic resistant bacteria in the world and is the most prevalent pathogen in cystic fibrosis (CF), causing chronic lung infections that are considered one of the major causes of mortality in CF patients. Although several studies have contributed to understanding P.a within-host adaptive evolution at a genomic level, it is still difficult to establish direct relationships between the observed mutations, expression of clinically relevant phenotypes, and clinical outcomes. Here, we performed a comparative untargeted LC/HRMS-based metabolomics analysis of sequential isolates from chronically infected CF patients to obtain a functional view of P.a adaptation. Metabolic profiles were integrated with expression of bacterial phenotypes and clinical measurements following multiscale analysis methods. Our results highlighted significant associations between P.a “metabotypes”, expression of antibiotic resistance and virulence phenotypes, and frequency of clinical exacerbations, thus identifying promising biomarkers and therapeutic targets for difficult-to-treat P.a infections

scholarly journals Rapid and robust evolution of collateral sensitivity in Pseudomonas aeruginosa antibiotic-resistant mutants

2020 ◽  
Vol 6 (32) ◽  
pp. eaba5493
Author(s):  
Sara Hernando-Amado ◽  
Fernando Sanz-García ◽  
José Luis Martínez
Keyword(s):  
Cystic Fibrosis ◽  
Pseudomonas Aeruginosa ◽  
Antibiotic Resistance ◽  
Rational Design ◽  
Antibiotic Resistant ◽  
Trade Off ◽  
Collateral Sensitivity ◽  
Trade Offs ◽  
Resistant Mutants ◽  
Antibiotic Resistant Mutants

The analysis of trade-offs, as collateral sensitivity, associated with the acquisition of antibiotic resistance, is mainly based on the use of model strains. However, the possibility of exploiting these trade-offs for fighting already resistant isolates has not been addressed in depth, despite the fact that bacterial pathogens are frequently antibiotic-resistant, forming either homogeneous or heterogeneous populations. Using a set of Pseudomonas aeruginosa-resistant mutants, we found that ceftazidime selects pyomelanogenic tobramycin-hypersusceptible mutants presenting chromosomal deletions in the analyzed genetic backgrounds. Since pyomelanogenic resistant mutants frequently coexist with other morphotypes in patients with cystic fibrosis, we analyzed the exploitation of this trade-off to drive extinction of heterogeneous resistant populations by using tobramycin/ceftazidime alternation. Our work shows that this approach is feasible because phenotypic trade-offs associated with the use of ceftazidime are robust. The identification of conserved collateral sensitivity networks may guide the rational design of evolution-based antibiotic therapies in P. aeruginosa infections.

Antibiotic susceptibility pattern against pathogenic bacteria causing Dental Caries

2011 ◽  
Vol 1 (1) ◽  
pp. 31-35
Author(s):  
Deepak Dwivedi ◽  
Tejram Kushwah ◽  
Mukesh Kushwah ◽  
Vinod Singh
Keyword(s):  
Dental Caries ◽  
Antibiotic Susceptibility ◽  
Pathogenic Bacteria ◽  
Resistant Bacteria ◽  
Susceptibility Pattern ◽  
Antibiotic Resistant ◽  
Antibiotic Susceptibility Pattern ◽  
Penicillin V ◽  
Antibiotics Susceptibility ◽  
Susceptibility Tests

Antibiotics to treat dental caries infection are routinely prescribed which led to the increased resistance against bacteria. The purpose of this investigation was to perform antibiotic susceptibility tests on a panel of pathogenic bacteria isolated from dental caries infection. Bacteria were isolated from caries site of patients and identified at the species level. Each of 150 species of bacteria was tested for antibiotics susceptibility to a five antibiotics using Etest. The antibiotics used were Amoxicillin, Cloxocillin, Erythromycin, Tetracycline and Penicillin‐V. The obtained resistance percentage for each antibiotic were Penicillin V: 72/150 (48%), Tetracycline: 99/150 (66%), Amoxicillin: 135/150 (90%), Cloxocillin: 117/150 (78%), and Erythromycin: 90/150 (60%) (Table 1). In case of combinatorial antibiotic exposure, the resistance percentage of Penicillin V/Amoxicillin and Amoxicillin/ Erythromycin was 39/150 (26%), and 45/150 (30%) respectively. The study has well demonstrated the clinical picture of antibiotic resistance and susceptibility pattern of bacteria causing dental caries. The obtained comprehensive data will allow investigating the spatial distribution of pathogenic, antibiotic resistant bacteria among dental caries patients which further may help into development of novel diagnostic and treatment approaches for the same.

scholarly journals Meropenem Combined with Ciprofloxacin Combats Hypermutable Pseudomonas aeruginosa from Respiratory Infections of Cystic Fibrosis Patients

2018 ◽  
Vol 62 (11) ◽  
Author(s):  
Vanessa E. Rees ◽  
Rajbharan Yadav ◽  
Kate E. Rogers ◽  
Jürgen B. Bulitta ◽  
Veronika Wirth ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Pseudomonas Aeruginosa ◽  
Time Course ◽  
Respiratory Infections ◽  
Resistant Bacteria ◽  
Infection Model ◽  
Time Curve ◽  
Bacterial Killing ◽  
Content Type ◽  
Concentration Time

ABSTRACT Hypermutable Pseudomonas aeruginosa organisms are prevalent in chronic respiratory infections and have been associated with reduced lung function in cystic fibrosis (CF); these isolates can become resistant to all antibiotics in monotherapy. This study aimed to evaluate the time course of bacterial killing and resistance of meropenem and ciprofloxacin in combination against hypermutable and nonhypermutable P. aeruginosa. Static concentration time-kill experiments over 72 h assessed meropenem and ciprofloxacin in mono- and combination therapies against PAO1 (nonhypermutable), PAOΔmutS (hypermutable), and hypermutable isolates CW8, CW35, and CW44 obtained from CF patients with chronic respiratory infections. Meropenem (1 or 2 g every 8 h [q8h] as 3-h infusions and 3 g/day as a continuous infusion) and ciprofloxacin (400 mg q8h as 1-h infusions) in monotherapies and combinations were further evaluated in an 8-day hollow-fiber infection model study (HFIM) against CW44. Concentration-time profiles in lung epithelial lining fluid reflecting the pharmacokinetics in CF patients were simulated and counts of total and resistant bacteria determined. All data were analyzed by mechanism-based modeling (MBM). In the HFIM, all monotherapies resulted in rapid regrowth with resistance at 48 h. The maximum daily doses of 6 g meropenem (T>MIC of 80% to 88%) and 1.2 g ciprofloxacin (area under the concentration-time curve over 24 h in the steady state divided by the MIC [AUC/MIC], 176), both given intermittently, in monotherapy failed to suppress regrowth and resulted in substantial emergence of resistance (≥7.6 log10 CFU/ml resistant populations). The combination of these regimens achieved synergistic killing and suppressed resistance. MBM with subpopulation and mechanistic synergy yielded unbiased and precise curve fits. Thus, the combination of 6 g/day meropenem plus ciprofloxacin holds promise for future clinical evaluation against infections by susceptible hypermutable P. aeruginosa.

scholarly journals Disruption of Cross-Feeding Inhibits Pathogen Growth in the Sputa of Patients with Cystic Fibrosis

mSphere ◽  
2020 ◽  
Vol 5 (2) ◽  
Author(s):  
Jeffrey M. Flynn ◽  
Lydia C. Cameron ◽  
Talia D. Wiggen ◽  
Jordan M. Dunitz ◽  
William R. Harcombe ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Pseudomonas Aeruginosa ◽  
Antibiotic Susceptibility ◽  
Susceptibility Testing ◽  
Anaerobic Bacteria ◽  
Content Type ◽  
Growth Environment ◽  
Polymicrobial Infections

ABSTRACT A critical limitation in the management of chronic polymicrobial infections is the lack of correlation between antibiotic susceptibility testing (AST) and patient responses to therapy. Underlying this disconnect is our inability to accurately recapitulate the in vivo environment and complex polymicrobial communities in vitro. However, emerging evidence suggests that, if modeled and tested accurately, interspecies relationships can be exploited by conventional antibiotics predicted to be ineffective by standard AST. As an example, under conditions where Pseudomonas aeruginosa relies on cocolonizing organisms for nutrients (i.e., cross-feeding), multidrug-resistant P. aeruginosa may be indirectly targeted by inhibiting the growth of its metabolic partners. While this has been shown in vitro using synthetic bacterial communities, the efficacy of a “weakest-link” approach to controlling host-associated polymicrobial infections has not yet been demonstrated. To test whether cross-feeding inhibition can be leveraged in clinically relevant contexts, we collected sputa from cystic fibrosis (CF) subjects and used enrichment culturing to isolate both P. aeruginosa and anaerobic bacteria from each sample. Predictably, both subpopulations showed various antibiotic susceptibilities when grown independently. However, when P. aeruginosa was cultured and treated under cooperative conditions in which it was dependent on anaerobic bacteria for nutrients, the growth of both the pathogen and the anaerobe was constrained despite their intrinsic antibiotic resistance profiles. These data demonstrate that the control of complex polymicrobial infections may be achieved by exploiting obligate or facultative interspecies relationships. Toward this end, in vitro susceptibility testing should evolve to more accurately reflect in vivo growth environments and microbial interactions found within them. IMPORTANCE Antibiotic efficacy achieved in vitro correlates poorly with clinical outcomes after treatment of chronic polymicrobial diseases; if a pathogen demonstrates susceptibility to a given antibiotic in the lab, that compound is often ineffective when administered clinically. Conversely, if a pathogen is resistant in vitro, patient treatment with that same compound can elicit a positive response. This discordance suggests that the in vivo growth environment impacts pathogen antibiotic susceptibility. Indeed, here we demonstrate that interspecies relationships among microbiotas in the sputa of cystic fibrosis patients can be targeted to indirectly inhibit the growth of Pseudomonas aeruginosa. The therapeutic implication is that control of chronic lung infections may be achieved by exploiting obligate or facultative relationships among airway bacterial community members. This strategy is particularly relevant for pathogens harboring intrinsic multidrug resistance and is broadly applicable to chronic polymicrobial airway, wound, and intra-abdominal infections.

scholarly journals In99, an In100-related integron, its occurrence and prevalence in clinical Pseudomonas aeruginosa strains from a central region of Portugal

2006 ◽  
Vol 135 (3) ◽  
pp. 502-504 ◽  
Author(s):  
T. CAETANO ◽  
S. FERREIRA ◽  
A. P. MONDEGO ◽  
A. CORREIA ◽  
S. MENDO
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Resistance Genes ◽  
Central Region ◽  
Clinical Isolates ◽  
Aminoglycoside Resistance ◽  
Class 1 Integron ◽  
Class 1 ◽  
Aminoglycoside Resistance Genes

In99, a possible ancestor of In100, is a class 1 integron associated with carbenicillinase (blaPSE) and aminoglycoside resistance genes [aac(6′)-Ib and aadA2]. In99 was present in 8 of 81 clinical isolates of Pseudomonas aeruginosa from unrelated patients collected in different years. The strains fell into two clonal groups and exhibited resistance to β-lactams and aminoglycosides.

scholarly journals Microbial Isolates from Vegetable Foreign Bodies Inhaled by Dogs

2018 ◽  
Vol 2018 ◽  
pp. 1-9 ◽  
Author(s):  
Sara Flisi ◽  
Manuel Dall’Aglio ◽  
Costanza Spadini ◽  
Clotilde Silvia Cabassi ◽  
Fausto Quintavalla
Keyword(s):  
Respiratory Tract ◽  
Antibiotic Susceptibility ◽  
Resistant Bacteria ◽  
Upper Respiratory Tract ◽  
Bacterial Strains ◽  
Antibiotic Resistant ◽  
E Coli ◽  
Bacteria And Fungi ◽  
Susceptibility Tests ◽  
The Right

Grass-seed inhalation is a common problem in canine patients, in particular during summer months, migrating in upper and lower respiratory tract. Grass awns can harbor bacteria and fungi, causing grass seeds foreign body-related disease (GSFBD). Aim of this study was to investigate the aerobic microbial flora isolated from grass awns extracted from 41 dogs with GSFBD and the antibiotic susceptibility of the isolated bacterial strains. Fifty-four grass awns were localized with diagnostic imaging tests and removed by endoscopy from respiratory tract. The most frequent localizations were in the left nostril and the right hemithorax. Only one grass awn was extracted from each patient except in 7 that had more than one. Bacteriological and mycological cultures, strains identification, and antibiotic susceptibility tests were performed. One or more bacterial strains were isolated from all grass awns. Fungal strains were isolated only in 4 cases. Staphylococcussp. was the most frequent isolate in the upper respiratory tract (36.8%), whileE. coli(24.4%) was the most frequent isolate in the lower tract. Fluoroquinolones and Doxycycline were the most effective antibiotics, while resistance was observed against Gentamicin (>93%), Cefapirin, and Clindamycin (>80%). These data are relevant in relation to the use of these antibiotics in both animals and humans, for the risk of transmission of antibiotic resistant bacteria or resistance genes.

scholarly journals Correction: Within-host whole genome analysis of an antibiotic resistant Pseudomonas aeruginosa strain sub-type in cystic fibrosis

PLoS ONE ◽  
2019 ◽  
Vol 14 (1) ◽  
pp. e0210929
Author(s):  
Laura J. Sherrard ◽  
Anna S. Tai ◽  
Bryan A. Wee ◽  
Kay A. Ramsay ◽  
Timothy J. Kidd ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Pseudomonas Aeruginosa ◽  
Genome Analysis ◽  
Whole Genome ◽  
Whole Genome Analysis ◽  
Antibiotic Resistant

scholarly journals Pseudomonas aeruginosa Susceptibility Patterns and Associated Clinical Outcomes in People with Cystic Fibrosis following Approval of Aztreonam Lysine for Inhalation

2020 ◽  
pp. AAC.02327-20 ◽  
Author(s):  
Claire L Keating ◽  
Jonathan B Zuckerman ◽  
Pradeep K Singh ◽  
Matthew McKevitt ◽  
Oksana Gurtovaya ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Pseudomonas Aeruginosa ◽  
Lung Function ◽  
Clinical Outcomes ◽  
Primary Endpoint ◽  
The United States ◽  
Study Endpoint ◽  
Primary Study ◽  
Antibiotic Exposure ◽  
Pulmonary Exacerbations

Rationale: Approval of aztreonam lysine for inhalation solution (AZLI) raised concerns that additional antibiotic exposure would potentially affect susceptibility profiles of Pseudomonas aeruginosa (PA) isolates from cystic fibrosis (CF) patients.Objective: This 5-year, prospective, observational study tracked susceptibility changes and clinical outcomes in CF patients in the United States with chronic PA infection.Methods: Sputum cultures were collected annually (2011-2016). The primary study endpoint was the proportion of subjects whose least susceptible PA isolate had an aztreonam minimum inhibitory concentration (MIC) that was >8 μg/mL (parenteral breakpoint) and increased ≥4-fold compared with the least susceptible isolate from the previous year. Annualized data for pulmonary exacerbations, hospitalizations, and FEV1% predicted were obtained from the CF Foundation Patient Registry and compared between subjects meeting/not meeting the primary endpoint.Results: 510 subjects were enrolled; 334 (65%) completed the study. A consistent proportion of evaluable subjects (13-22%) met the primary endpoint each year; and AZLI use during the previous 12 months was not associated with meeting the primary endpoint. While the annual decline in lung function was comparable for subjects meeting/not meeting the primary endpoint, more pulmonary exacerbations and hospitalizations were experienced by those who met it.Conclusions: Aztreonam susceptibility of PA remained consistent during the 5-year study. The relationship between PA isolate susceptibilities and clinical outcomes is complex; reduced susceptibility was not associated with accelerated decline in lung function, but was associated with more exacerbations and hospitalizations, likely reflecting increased overall antibiotic exposure.

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