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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.
Eur J Clin Invest ; 51(12): e13687, 2021 Dec.
Article in English | MEDLINE | ID: covidwho-1443255

ABSTRACT

BACKGROUND/OBJECTIVES: We investigated whether behavioral precautions adopted during Coronavirus disease (COVID-19) pandemic also influenced the spreading and multidrug resistance (MDR) of ESKAPEEc (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii [AB], Pseudomonas aeruginosa, Enterobacter spp and Escherichia Coli, [EC]) among Intensive Care Unit (ICU) patients. SUBJECTS/METHODS: We performed a single-center retrospective study in adult patients admitted to our COVID-19-free surgical ICU. Only patients staying in ICU for more than 48 hours were included. The ESKAPEEc infections recorded during the COVID-19 period (June 1, 2020 - February 28, 2021) and in the corresponding pre-pandemic period (June 1, 2019 - February 28, 2020) were compared. An interrupted time series analysis was performed to rule out possible confounders. RESULTS: Overall, 173 patients in the COVID-19 period and 132 in the pre-COVID-19 period were investigated. The ESKAPEEc infections were documented in 23 (13.3%) and 35 (26.5%) patients in the pandemic and the pre-pandemic periods, respectively (p = 0.005). Demographics, diagnosis, comorbidities, type of surgery, Simplified Acute Physiology Score II, length of mechanical ventilation, hospital and ICU length of stay, ICU death rate, and 28-day hospital mortality were similar in the two groups. In comparison with the pre-pandemic period, no AB was recorded during COVID-19 period, (p = 0.017), while extended-spectrum beta-lactamase-producing EC infections significantly decreased (p = 0.017). Overall, the ESKAPEEc isolates during pandemic less frequently exhibited multidrug-resistant (p = 0.014). CONCLUSIONS: These findings suggest that a robust adherence to hygiene measures together with human contact restrictions in a COVID-19 free ICU might also restrain the transmission of ESKAPEEc pathogens.


Subject(s)
COVID-19/prevention & control , Cross Infection/epidemiology , Gram-Negative Bacterial Infections/epidemiology , Gram-Positive Bacterial Infections/epidemiology , Infection Control , Acinetobacter Infections/epidemiology , Acinetobacter Infections/microbiology , Acinetobacter Infections/transmission , Acinetobacter baumannii , Aged , Cross Infection/microbiology , Cross Infection/transmission , Drug Resistance, Multiple, Bacterial , Enterobacter , Enterobacteriaceae Infections/epidemiology , Enterobacteriaceae Infections/microbiology , Enterobacteriaceae Infections/transmission , Enterococcus faecium , Escherichia coli Infections/epidemiology , Escherichia coli Infections/microbiology , Escherichia coli Infections/transmission , Female , Gram-Negative Bacterial Infections/microbiology , Gram-Negative Bacterial Infections/transmission , Gram-Positive Bacterial Infections/microbiology , Gram-Positive Bacterial Infections/transmission , Hand Disinfection , Humans , Intensive Care Units , Interrupted Time Series Analysis , Klebsiella Infections/epidemiology , Klebsiella Infections/microbiology , Klebsiella Infections/transmission , Klebsiella pneumoniae , Male , Methicillin-Resistant Staphylococcus aureus , Middle Aged , Organizational Policy , Personal Protective Equipment , Pseudomonas Infections/epidemiology , Pseudomonas Infections/microbiology , Pseudomonas Infections/transmission , Pseudomonas aeruginosa , Retrospective Studies , SARS-CoV-2 , Staphylococcal Infections/epidemiology , Staphylococcal Infections/microbiology , Staphylococcal Infections/transmission , Staphylococcus aureus , Visitors to Patients
4.
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
5.
Cell Rep ; 36(9): 109637, 2021 08 31.
Article in English | MEDLINE | ID: covidwho-1356160

ABSTRACT

Research conducted on severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pathogenesis and coronavirus disease 2019 (COVID-19) generally focuses on the systemic host response, especially that generated by severely ill patients, with few studies investigating the impact of acute SARS-CoV-2 at the site of infection. We show that the nasal microbiome of SARS-CoV-2-positive patients (CoV+, n = 68) at the time of diagnosis is unique when compared to CoV- healthcare workers (n = 45) and CoV- outpatients (n = 21). This shift is marked by an increased abundance of bacterial pathogens, including Pseudomonas aeruginosa, which is also positively associated with viral RNA load. Additionally, we observe a robust host transcriptional response in the nasal epithelia of CoV+ patients, indicative of an antiviral innate immune response and neuronal damage. These data suggest that the inflammatory response caused by SARS-CoV-2 infection is associated with an increased abundance of bacterial pathogens in the nasal cavity that could contribute to increased incidence of secondary bacterial infections.


Subject(s)
Bacteria/classification , Bacterial Infections/microbiology , COVID-19 , Microbiota , Adult , Aged , Aged, 80 and over , Bacteria/isolation & purification , COVID-19/complications , COVID-19/immunology , COVID-19/microbiology , Coinfection/microbiology , Coinfection/virology , Cross-Sectional Studies , DNA, Bacterial/genetics , Female , Humans , Immunity, Innate , Inflammation , Male , Middle Aged , Nose/microbiology , Pseudomonas Infections/microbiology , Pseudomonas aeruginosa/isolation & purification , RNA, Ribosomal, 16S/genetics , RNA, Viral/genetics , RNA-Seq , Transcriptome , Viral Load , Young Adult
6.
Eur J Clin Microbiol Infect Dis ; 40(2): 373-379, 2021 Feb.
Article in English | MEDLINE | ID: covidwho-1033857

ABSTRACT

Quorum sensing (QS) inhibition is an essential strategy to combat bacterial infection. Previously, we have synthesized a series of thymidine derivatives bearing isoxazole and 1,2,3-triazole rings (TITL). Herein, the inhibitory effects of TITL on QS of Pseudomonas aeruginosa PAO1 were evaluated. In vitro results demonstrated that TITL effectively inhibited biofilm formation and reduced the virulence factors of P. aeruginosa PAO1. In combination with antibiotics, our TITL compounds significantly prolonged the lifespans of Caenorhabditis elegans N2 nematodes that were infected with P. aeruginosa PAO1 in vivo. In conclusion, TITL compounds are promising candidates for the treatment of antibiotic-resistant P. aeruginosa PAO1.


Subject(s)
Biofilms/drug effects , Pseudomonas Infections/microbiology , Pseudomonas aeruginosa/drug effects , Quorum Sensing/drug effects , Triazoles/pharmacology , Virulence/drug effects , Animals , Anti-Bacterial Agents/pharmacology , Caenorhabditis elegans , Drug Resistance, Bacterial
7.
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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