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1.
Eur J Clin Microbiol Infect Dis ; 41(1): 53-62, 2022 Jan.
Article in English | MEDLINE | ID: covidwho-1616163

ABSTRACT

There is relatively little contemporary information regarding clinical characteristics of patients with Pseudomonas aeruginosa bacteremia (PAB) in the community hospital setting. This was a retrospective, observational cohort study examining the clinical characteristics of patients with PAB across several community hospitals in the USA with a focus on the appropriateness of initial empirical therapy and impact on patient outcomes. Cases of PAB occurring between 2016 and 2019 were pulled from 8 community medical centers. Patients were classified as having either positive or negative outcome at hospital discharge. Several variables including receipt of active empiric therapy (AET) and the time to receiving AET were collected. Variables with a p value of < 0.05 in univariate analyses were included in a multivariable logistic regression model. Two hundred and eleven episodes of PAB were included in the analysis. AET was given to 81.5% of patients and there was no difference in regard to outcome (p = 0.62). There was no difference in the median time to AET in patients with a positive or negative outcome (p = 0.53). After controlling for other variables, age, Pitt bacteremia score ≥ 4, and septic shock were independently associated with a negative outcome. A high proportion of patients received timely, active antimicrobial therapy for PAB and time to AET did not have a significant impact on patient outcome.


Subject(s)
Anti-Bacterial Agents/therapeutic use , Bacteremia/drug therapy , Pseudomonas Infections/drug therapy , Pseudomonas aeruginosa/drug effects , Aged , Bacteremia/microbiology , Female , Hospitals, Community/statistics & numerical data , Humans , Male , Middle Aged , Pseudomonas Infections/microbiology , Pseudomonas aeruginosa/genetics , Pseudomonas aeruginosa/isolation & purification , Pseudomonas aeruginosa/physiology , Retrospective Studies
2.
Science ; 372(6547): 1169-1175, 2021 06 11.
Article in English | MEDLINE | ID: covidwho-1583231

ABSTRACT

Emergent resistance to all clinical antibiotics calls for the next generation of therapeutics. Here we report an effective antimicrobial strategy targeting the bacterial hydrogen sulfide (H2S)-mediated defense system. We identified cystathionine γ-lyase (CSE) as the primary generator of H2S in two major human pathogens, Staphylococcus aureus and Pseudomonas aeruginosa, and discovered small molecules that inhibit bacterial CSE. These inhibitors potentiate bactericidal antibiotics against both pathogens in vitro and in mouse models of infection. CSE inhibitors also suppress bacterial tolerance, disrupting biofilm formation and substantially reducing the number of persister bacteria that survive antibiotic treatment. Our results establish bacterial H2S as a multifunctional defense factor and CSE as a drug target for versatile antibiotic enhancers.


Subject(s)
Anti-Bacterial Agents/pharmacology , Cystathionine gamma-Lyase/antagonists & inhibitors , Enzyme Inhibitors/pharmacology , Hydrogen Sulfide/metabolism , Pseudomonas aeruginosa/drug effects , Staphylococcus aureus/drug effects , Animals , Anti-Bacterial Agents/chemistry , Anti-Bacterial Agents/metabolism , Biofilms , Crystallography, X-Ray , Cystathionine gamma-Lyase/chemistry , Cystathionine gamma-Lyase/genetics , Cystathionine gamma-Lyase/metabolism , Drug Discovery , Drug Resistance, Bacterial , Drug Synergism , Drug Tolerance , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/metabolism , Mice , Microbial Sensitivity Tests , Models, Molecular , Molecular Docking Simulation , Molecular Structure , Pseudomonas Infections/drug therapy , Pseudomonas Infections/microbiology , Pseudomonas aeruginosa/enzymology , Pseudomonas aeruginosa/genetics , Pseudomonas aeruginosa/growth & development , Small Molecule Libraries/chemistry , Small Molecule Libraries/metabolism , Small Molecule Libraries/pharmacology , Staphylococcal Infections/drug therapy , Staphylococcal Infections/microbiology , Staphylococcus aureus/enzymology , Staphylococcus aureus/genetics , Staphylococcus aureus/growth & development
3.
Ann Clin Microbiol Antimicrob ; 20(1): 64, 2021 Sep 07.
Article in English | MEDLINE | ID: covidwho-1398863

ABSTRACT

BACKGROUND: Bacterial superinfections associated with COVID-19 are common in ventilated ICU patients and impact morbidity and lethality. However, the contribution of antimicrobial resistance to the manifestation of bacterial infections in these patients has yet to be elucidated. METHODS: We collected 70 Gram-negative bacterial strains, isolated from the lower respiratory tract of ventilated COVID-19 patients in Zurich, Switzerland between March and May 2020. Species identification was performed using MALDI-TOF; antibiotic susceptibility profiles were determined by EUCAST disk diffusion and CLSI broth microdilution assays. Selected Pseudomonas aeruginosa isolates were analyzed by whole-genome sequencing. RESULTS: Pseudomonas aeruginosa (46%) and Enterobacterales (36%) comprised the two largest etiologic groups. Drug resistance in P. aeruginosa isolates was high for piperacillin/tazobactam (65.6%), cefepime (56.3%), ceftazidime (46.9%) and meropenem (50.0%). Enterobacterales isolates showed slightly lower levels of resistance to piperacillin/tazobactam (32%), ceftriaxone (32%), and ceftazidime (36%). All P. aeruginosa isolates and 96% of Enterobacterales isolates were susceptible to aminoglycosides, with apramycin found to provide best-in-class coverage. Genotypic analysis of consecutive P. aeruginosa isolates in one patient revealed a frameshift mutation in the transcriptional regulator nalC that coincided with a phenotypic shift in susceptibility to ß-lactams and quinolones. CONCLUSIONS: Considerable levels of antimicrobial resistance may have contributed to the manifestation of bacterial superinfections in ventilated COVID-19 patients, and may in some cases mandate consecutive adaptation of antibiotic therapy. High susceptibility to amikacin and apramycin suggests that aminoglycosides may remain an effective second-line treatment of ventilator-associated bacterial pneumonia, provided efficacious drug exposure in lungs can be achieved.


Subject(s)
Anti-Bacterial Agents/pharmacology , COVID-19/microbiology , Gram-Negative Bacteria/drug effects , Respiratory System/microbiology , COVID-19/complications , Drug Resistance, Multiple, Bacterial/drug effects , Gram-Negative Bacteria/isolation & purification , Humans , Microbial Sensitivity Tests , Pneumonia, Ventilator-Associated/microbiology , Prospective Studies , Pseudomonas Infections/microbiology , Pseudomonas aeruginosa/drug effects , Pseudomonas aeruginosa/genetics , Pseudomonas aeruginosa/isolation & purification , SARS-CoV-2/isolation & purification , Switzerland
4.
Antimicrob Agents Chemother ; 65(8): e0008921, 2021 07 16.
Article in English | MEDLINE | ID: covidwho-1315793

ABSTRACT

A ceftolozane-tazobactam- and ceftazime-avibactam-resistant Pseudomonas aeruginosa isolate was recovered after treatment (including azithromycin, meropenem, and ceftolozane-tazobactam) from a patient that had developed ventilator-associated pneumonia after COVID-19 infection. Whole-genome sequencing revealed that the strain, belonging to ST274, had acquired a nonsense mutation leading to truncated carbapenem porin OprD (W277X), a 7-bp deletion (nt213Δ7) in NfxB (negative regulator of the efflux pump MexCD-OprJ), and two missense mutations (Q178R and S133G) located within the first large periplasmic loop of MexD. Through the construction of mexD mutants and complementation assays with wild-type nfxB, it was evidenced that resistance to the novel cephalosporin-ß-lactamase inhibitor combinations was caused by the modification of MexD substrate specificity.


Subject(s)
COVID-19 , Pseudomonas Infections , Anti-Bacterial Agents/pharmacology , Anti-Bacterial Agents/therapeutic use , Cephalosporinase , Cephalosporins/pharmacology , Humans , Microbial Sensitivity Tests , Pseudomonas , Pseudomonas Infections/drug therapy , Pseudomonas aeruginosa/genetics , SARS-CoV-2 , beta-Lactamase Inhibitors/pharmacology
5.
Front Cell Infect Microbiol ; 11: 641920, 2021.
Article in English | MEDLINE | ID: covidwho-1170079

ABSTRACT

Pseudomonas aeruginosa is a biofilm-forming opportunistic pathogen which causes chronic infections in immunocompromised patients and leads to high mortality rate. It is identified as a common coinfecting pathogen in COVID-19 patients causing exacerbation of illness. In our hospital, P. aeruginosa is one of the top coinfecting bacteria identified among COVID-19 patients. We collected a strong biofilm-forming P. aeruginosa strain displaying small colony variant morphology from a severe COVID-19 patient. Genomic and transcriptomic sequencing analyses were performed with phenotypic validation to investigate its adaptation in SARS-CoV-2 infected environment. Genomic characterization predicted specific genomic islands highly associated with virulence, transcriptional regulation, and DNA restriction-modification systems. Epigenetic analysis revealed a specific N6-methyl adenine (m6A) methylating pattern including methylation of alginate, flagellar and quorum sensing associated genes. Differential gene expression analysis indicated that this isolate formed excessive biofilm by reducing flagellar formation (7.4 to 1,624.1 folds) and overproducing extracellular matrix components including CdrA (4.4 folds), alginate (5.2 to 29.1 folds) and Pel (4.8-5.5 folds). In summary, we demonstrated that P. aeuginosa clinical isolates with novel epigenetic markers could form excessive biofilm, which might enhance its antibiotic resistance and in vivo colonization in COVID-19 patients.


Subject(s)
Adaptation, Physiological/physiology , COVID-19/complications , Coinfection/complications , Pseudomonas Infections/complications , Pseudomonas aeruginosa/genetics , Pseudomonas aeruginosa/metabolism , Adhesins, Bacterial/genetics , Adhesins, Bacterial/metabolism , Alginates , Bacteria , Biofilms/growth & development , DNA Methylation , Epigenomics , Gene Expression Profiling , Gene Expression Regulation, Bacterial , Genome, Bacterial , Humans , Pseudomonas Infections/immunology , Pseudomonas Infections/microbiology , Pseudomonas aeruginosa/classification , Quorum Sensing/genetics , SARS-CoV-2 , Transcriptome , Virulence
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