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Annals of Intensive Care Jun 2023Appropriate antibiotic treatment for critically ill patients with serious Gram-negative infections in the intensive care unit is crucial to minimize morbidity and... (Review)
Review
Appropriate antibiotic treatment for critically ill patients with serious Gram-negative infections in the intensive care unit is crucial to minimize morbidity and mortality. Several new antibiotics have shown in vitro activity against carbapenem-resistant Enterobacterales (CRE) and difficult-to-treat resistant Pseudomonas aeruginosa. Cefiderocol is the first approved siderophore beta-lactam antibiotic with potent activity against multidrug-resistant, carbapenem-resistant, difficult-to-treat or extensively drug-resistant Gram-negative pathogens, which have limited treatment options. The spectrum of activity of cefiderocol includes drug-resistant strains of Acinetobacter baumannii, P. aeruginosa, Stenotrophomonas maltophilia, Achromobacter spp. and Burkholderia spp. and CRE that produce serine- and/or metallo-carbapenemases. Phase 1 studies established that cefiderocol achieves adequate concentration in the epithelial lining fluid in the lung and requires dosing adjustment for renal function, including patients with augmented renal clearance and continuous renal-replacement therapy (CRRT); no clinically significant drug-drug interactions are expected. The non-inferiority of cefiderocol versus high-dose, extended-infusion meropenem in all-cause mortality (ACM) rates at day 14 was demonstrated in the randomized, double-blind APEKS-NP Phase 3 clinical study in patients with nosocomial pneumonia caused by suspected or confirmed Gram-negative bacteria. Furthermore, the efficacy of cefiderocol was investigated in the randomized, open-label, pathogen-focused, descriptive CREDIBLE-CR Phase 3 clinical study in its target patient population with serious carbapenem-resistant Gram-negative infections, including hospitalized patients with nosocomial pneumonia, bloodstream infection/sepsis, or complicated urinary tract infections. However, a numerically greater ACM rate with cefiderocol compared with BAT led to the inclusion of a warning in US and European prescribing information. Cefiderocol susceptibility results obtained with commercial tests should be carefully evaluated due to current issues regarding their accuracy and reliability. Since its approval, real-world evidence in patients with multidrug-resistant and carbapenem-resistant Gram-negative bacterial infections suggests that cefiderocol can be efficacious in certain critically ill patient groups, such as those requiring mechanical ventilation for COVID-19 pneumonia with subsequently acquired Gram-negative bacterial superinfection, and patients with CRRT and/or extracorporeal membrane oxygenation. In this article, we review the microbiological spectrum, pharmacokinetics/pharmacodynamics, efficacy and safety profiles and real-world evidence for cefiderocol, and look at future considerations for its role in the treatment of critically ill patients with challenging Gram-negative bacterial infections.
PubMed: 37322293
DOI: 10.1186/s13613-023-01146-5 -
and activity of cefiderocol against spp. and complex, including carbapenem-non-susceptible isolates.Antimicrobial Agents and Chemotherapy Dec 2023spp. and complex (Bcc) are rare but diverse opportunistic pathogens associated with serious infections, which are often multidrug resistant. This study compared the...
spp. and complex (Bcc) are rare but diverse opportunistic pathogens associated with serious infections, which are often multidrug resistant. This study compared the antibacterial activity of the siderophore antibiotic cefiderocol against spp. and Bcc isolates with that of other approved antibacterial drugs, including ceftazidime-avibactam, ciprofloxacin, colistin, imipenem-relebactam, and meropenem-vaborbactam. Isolates were collected in the SIDERO multinational surveillance program. Among 334 spp. isolates [76.6% from respiratory tract infections (RTIs)], cefiderocol had minimum inhibitory concentration (MIC) of 0.06/0.5 µg/mL overall and 0.5/4 µg/mL against 52 (15.6%) carbapenem-non-susceptible (Carb-NS) isolates. Eleven (3.3%) spp. isolates overall and 6 (11.5%) Carb-NS isolates were not susceptible to cefiderocol. Among 425 Bcc isolates (73.4% from RTIs), cefiderocol had MIC of ≤0.03/0.5 µg/mL overall and ≤0.03/1 µg/mL against 184 (43.3%) Carb-NS isolates. Twenty-two (5.2%) Bcc isolates overall and 13 (7.1%) Carb-NS isolates were not susceptible to cefiderocol. Cumulative MIC distributions showed cefiderocol to be the most active of the agents tested against both spp. and Bcc. In a neutropenic murine lung infection model and a humanized pharmacokinetic immunocompetent rat lung infection model, cefiderocol showed significant bactericidal activity against two meropenem-resistant strains compared with untreated controls ( < 0.05) and vehicle-treated controls ( < 0.05), respectively. Meropenem, piperacillin-tazobactam, ceftazidime, and ciprofloxacin comparators showed no significant activity in these models. The results suggest that cefiderocol could be a possible treatment option for RTIs caused by spp. and Bcc.
Topics: Rats; Animals; Mice; Cefiderocol; Meropenem; Carbapenems; Cephalosporins; Burkholderia cepacia complex; Achromobacter; Drug Resistance, Multiple, Bacterial; Anti-Bacterial Agents; Ceftazidime; Respiratory Tract Infections; Ciprofloxacin; Microbial Sensitivity Tests
PubMed: 37971240
DOI: 10.1128/aac.00346-23 -
Viruses Jul 2023species colonization of Cystic Fibrosis respiratory airways is an increasing concern. Two adult patients with Cystic Fibrosis colonized by CF418 or CF116 experienced...
species colonization of Cystic Fibrosis respiratory airways is an increasing concern. Two adult patients with Cystic Fibrosis colonized by CF418 or CF116 experienced fatal exacerbations. spp. are naturally resistant to several antibiotics. Therefore, phages could be valuable as therapeutics for the control of . In this study, thirteen lytic phages were isolated and characterized at the morphological and genomic levels for potential future use in phage therapy. They are presented here as the Kumeyaay phage collection. Six distinct phage genome clusters were identified based on a comprehensive phylogenetic analysis of the Kumeyaay collection as well as the publicly available phages. The infectivity of all phages in the Kumeyaay collection was tested in 23 clinical isolates; 78% of these isolates were lysed by at least one phage. A cryptic prophage was induced in CF418 when infected with some of the lytic phages. This prophage genome was characterized and is presented as phage CF418-P1. Prophage induction during lytic phage preparation for therapy interventions require further exploration. Large-scale production of phages and removal of endotoxins using an octanol-based procedure resulted in a phage concentrate of 1 × 10 plaque-forming units per milliliter with an endotoxin concentration of 65 endotoxin units per milliliter, which is below the Food and Drugs Administration recommended maximum threshold for human administration. This study provides a comprehensive framework for the isolation, bioinformatic characterization, and safe production of phages to kill spp. in order to potentially manage Cystic Fibrosis (CF) pulmonary infections.
Topics: Adult; Humans; Bacteriophages; Cystic Fibrosis; Phylogeny; Achromobacter; Achromobacter denitrificans; Prophages; Endotoxins
PubMed: 37632008
DOI: 10.3390/v15081665 -
Antimicrobial Agents and Chemotherapy Jul 2023We conducted antimicrobial susceptibility testing of 267 isolates for 16 antibiotics from 2017 to 2022. The highest susceptibility was found for...
We conducted antimicrobial susceptibility testing of 267 isolates for 16 antibiotics from 2017 to 2022. The highest susceptibility was found for piperacillin-tazobactam (70%) and ceftazidime-avibactam (62%). Between 30% and 49% of strains were susceptible to tigecycline, ceftazidime, and meropenem. We applied species-specific Achromobacter xylosoxidans breakpoints for piperacillin-tazobactam, meropenem, and trimethoprim-sulfamethoxazole and EUCAST pharmacokinetic/pharmacodynamic (PK/PD) breakpoints for the others. A. xylosoxidans was the most frequently isolated species, followed by Achromobacter insuavis and Achromobacter ruhlandii.
Topics: Humans; Meropenem; Cystic Fibrosis; Microbial Sensitivity Tests; Anti-Bacterial Agents; Achromobacter; Piperacillin; Tazobactam
PubMed: 37310234
DOI: 10.1128/aac.00379-23 -
Cell Reports Aug 2023How the opportunistic Gram-negative pathogens of the genus Achromobacter interact with the innate immune system is poorly understood. Using three Achromobacter clinical...
How the opportunistic Gram-negative pathogens of the genus Achromobacter interact with the innate immune system is poorly understood. Using three Achromobacter clinical isolates from two species, we show that the type 3 secretion system (T3SS) is required to induce cell death in human macrophages by inflammasome-dependent pyroptosis. Macrophages deficient in the inflammasome sensors NLRC4 or NLRP3 undergo pyroptosis upon bacterial internalization, but those deficient in both NLRC4 and NLRP3 do not, suggesting either sensor mediates pyroptosis in a T3SS-dependent manner. Detailed analysis of the intracellular trafficking of one isolate indicates that the intracellular bacteria reside in a late phagolysosome. Using an intranasal mouse infection model, we observe that Achromobacter damages lung structure and causes severe illness, contingent on a functional T3SS. Together, we demonstrate that Achromobacter species can survive phagocytosis by promoting macrophage cell death and inflammation by redundant mechanisms of pyroptosis induction in a T3SS-dependent manner.
Topics: Humans; Animals; Mice; Pyroptosis; Inflammasomes; NLR Family, Pyrin Domain-Containing 3 Protein; Type III Secretion Systems; Achromobacter; Disease Models, Animal; Calcium-Binding Proteins; CARD Signaling Adaptor Proteins
PubMed: 37598340
DOI: 10.1016/j.celrep.2023.113012 -
Microbiology Spectrum Mar 2024spp. are opportunistic pathogens of environmental origin increasingly isolated in patients with underlying conditions like cystic fibrosis (CF). Despite recent...
UNLABELLED
spp. are opportunistic pathogens of environmental origin increasingly isolated in patients with underlying conditions like cystic fibrosis (CF). Despite recent advances, their virulence factors remain incompletely studied, and siderophore production has not yet been investigated in this genus. The aim of this study was to evaluate the production of siderophores in a large collection of spp. and evaluate the variability according to the origin of the strain and species. A total of 163 strains were studied, including 128 clinical strains (CF and non-CF patients) and 35 strains of environmental origin. Siderophores were quantified by the liquid chrome azurol-sulphonate assay. Species were identified by gene-based phylogeny. Strains were assigned to 20 species, with being the most represented (51.5% of strains). Siderophore production was observed in 72.4% of the strains, with amounts ranging from 10.1% to 90% siderophore units. A significantly higher prevalence of siderophore-producing strains and greater production of siderophores were observed for clinical strains compared with strains of environmental origin. Highly variable observations were made according to species: presented unique characteristics (one of the highest prevalence of producing strains and highest amounts produced, particularly by CF strains). Siderophores are important factors for bacterial growth commonly produced by members of the genus. The significance of the observations made during this study must be further investigated. Indeed, the differences observed according to species and the origin of strains suggest that siderophores may represent important determinants of the pathophysiology of spp. infections and also contribute to the particular epidemiological success of in human infections.
IMPORTANCE
spp. are recognized as emerging opportunistic pathogens in humans with various underlying diseases, including cystic fibrosis (CF). Although their pathophysiological traits are increasingly studied, their virulence factors remain incompletely described. Particularly, siderophores that represent important factors of bacterial growth have not yet been studied in this genus. A population-based study was performed to explore the ability of members of the genus to produce siderophores, both overall and in relevant subgroups ( species; strain origin, either clinical-from CF or non-CF patients-or environmental). This study provides original data showing that siderophore production is a common trait of strains, particularly observed among clinical strains. The major species, , encompassed both one of the highest prevalence of siderophore-producing strains and strains producing the largest amounts of siderophores, particularly observed for CF strains. These observations may represent additional advantages accounting for the epidemiological success of this species.
Topics: Humans; Achromobacter; Cystic Fibrosis; Prevalence; Gram-Negative Bacterial Infections; Achromobacter denitrificans; Virulence Factors; Siderophores
PubMed: 38315029
DOI: 10.1128/spectrum.02953-23 -
Environment International Aug 2023The influence of vertical changes in water depth on emerging pollutants distribution and microbial food web remains elusive. We investigated the influence of vertical...
Vertical changes in water depth and environmental variables drove the antibiotics and antibiotic resistomes distribution, and microbial food web structures in the estuary and marine ecosystems.
The influence of vertical changes in water depth on emerging pollutants distribution and microbial food web remains elusive. We investigated the influence of vertical transition in water depth on the environmental variables, antibiotics and antibiotic resistomes, and microbial community structures in estuary and marine ecosystems (0-50 m). Stepwise multiple linear regression model showed that among investigated environmental variables, change in water salinity was the most influential factor dictating the fluoroquinolone and macrolides concentrations, while dissolved oxygen and turbidity were the key influencers of sulfonamides and beta-lactam concentrations, respectively. Bacterial and eukaryotic diversity and niche breadth significantly increased with the increasing water depth. Ecosystem food web structure at the bottom depths was more stable than at the middle and surface depths. At the surface depth, the top 5 keystone genera were Cryothecomonas, Syndiniales, Achromobacter, Pseudopirsonia, and Karlodinium. Whereas Eugregarinorida, Neptuniibacter, Mychonastes, Novel_Apicomplexa_Class_1, Aplanochytrium and Dietzia, Halodaphnea, Luminiphilus, Aplanochytrium, Maullinia dominated the top 5 genera at the middle and the bottom depth, respectively. Absolute abundance of antibiotic resistance genes (ARGs) was drastically increased at the surface depth compared with the middle and bottom depths. Abundance of the top 10 ARGs and mobile genetic elements (MGEs) detected including tnpA-05, aadA2-03, mexF, aadA1, intI-1(clinic), qacEdelta1-02, aadA-02, qacEdelta1-01, cmlA1-01, and aadA-01 were amplified at the surface depth. This study demonstrated that ARGs abundance was disproportionate to bacterial diversity, and anthropogenic disturbances, confinement, MGEs, and ecosystem stability play primary roles in the fate of ARGs. The findings of this study also implicate that vertical changes in the water depth on environmental conditions can influence antibiotic concentrations and microbial community dramatically.
Topics: Anti-Bacterial Agents; Water; Food Chain; Genes, Bacterial; Estuaries; Bacteria; Microbiota
PubMed: 37517178
DOI: 10.1016/j.envint.2023.108118 -
Access Microbiology 2023is a Gram-negative, motile, obligate aerobic and non-fermentative bacterium. It is an emerging pathogen in the hospital environment as it is frequently found in various...
INTRODUCTION
is a Gram-negative, motile, obligate aerobic and non-fermentative bacterium. It is an emerging pathogen in the hospital environment as it is frequently found in various solutions.
HYPOTHESIS/GAP STATEMENT
Information about the incidence and risk factors of bacteremia from India is limited.
AIM
We conducted this study to identify the risk factors and underlying conditions predisposing to bacteremia by spp. and analyse the antibiotic resistance pattern of the isolates.
METHODOLOGY
We performed a retrospective observational study where automated blood cultures positive for spp. were assessed for clinical characteristics and antibiotic susceptibility patterns from January 2022 to December 2022 in the microbiology laboratory of a tertiary care centre in Northern India.
RESULTS
A total of 14 cases (14/2435, 0.57 %) of spp. were identified from bloodstream infections in one year. The mean age of the patients was 37.59±23.17 years with a male predominance (8/14, 57.1 %). All patients were managed on intravenous antibiotics and intravenous access as peripheral line catheters and only 5(5/14, 35.7 %) patients were managed on central line catheters. The isolates were found highly susceptible to ticarcillin-clavulanic acid (14/14, 100.0 %) followed by fluoroquinolones (12/14, 85.72 %) and trimethoprim-sulphamethoxazole (12/14, 85.72 %). Only 57.14 % (8/14, 57.14 %) of the patients were susceptible to piperacillin-tazobactam. The all-cause 40 day mortality was observed in 35.7 % (5/14, 35.7 %) with two deaths that were directly attributable to sepsis.
CONCLUSION
This study provides insight into the incidence of bacteremia at our centre and the necessary antibiotic therapy to combat it.
PubMed: 37841106
DOI: 10.1099/acmi.0.000588.v3 -
Microbiology Spectrum Aug 2023Wildlife can be a reservoir and source of zoonotic pathogens for humans. For instance, pangolins were considered one of the potential animal reservoirs of SARS-CoV-2....
Wildlife can be a reservoir and source of zoonotic pathogens for humans. For instance, pangolins were considered one of the potential animal reservoirs of SARS-CoV-2. The aim of this study was to assess the prevalence of antimicrobial-resistant species (e.g., extended-spectrum β-lactamase [ESBL]-producing ) and Staphylococcus aureus-related complex and to describe the bacterial community in wild Gabonese pangolins. The pharyngeal colonization of pangolins sold in Gabon ( = 89, 2021 to 2022) was analyzed using culture media selective for ESBL-producing , S. aureus-related complex, Gram-positive bacteria and nonfermenters. Phylogenetic analyses of ESBL-producing was done using core-genome multilocus sequence typing (cgMLST) and compared with publicly available genomes. Patterns of cooccurring species were detected by network analysis. Of the 439 bacterial isolates, the majority of species belonged to the genus Pseudomonas ( = 170), followed by ( = 113) and ( = 37). Three Klebsiella pneumoniae isolates and one Escherichia coli isolate were ESBL-producers, which clustered with human isolates from Nigeria (MLST sequence type 1788 [ST1788]) and Gabon (ST38), respectively. Network analysis revealed a frequent cooccurrence of Stenotrophomonas maltophilia with Pseudomonas putida and Pseudomonas aeruginosa. In conclusion, pangolins can be colonized with human-related ESBL-producing K. pneumoniae and E. coli. Unlike in other African wildlife, S. aureus-related complex was not detected in pangolins. There is an ongoing debate if pangolins are a relevant reservoir for viruses such as SARS-CoV-2. Here, we wanted to know if African pangolins are colonized with bacteria that are relevant for human health. A wildlife reservoir of antimicrobial resistance would be of medical relevance in regions were consumption of so-called bushmeat is common. In 89 pangolins, we found three ESBL-producing Klebsiella pneumoniae strains and one ESBL-producing Escherichia coli strains, which were closely related to isolates from humans in Africa. This points toward either a transmission between pangolins and humans or a common source from which both humans and pangolins became colonized.
Topics: Animals; Humans; Anti-Bacterial Agents; Escherichia coli; Pangolins; Multilocus Sequence Typing; Gabon; Staphylococcus aureus; Phylogeny; beta-Lactamases; Drug Resistance, Bacterial; COVID-19; SARS-CoV-2; Escherichia coli Infections; Klebsiella pneumoniae; Bacteria; Microbial Sensitivity Tests
PubMed: 37338382
DOI: 10.1128/spectrum.00664-23 -
Microbiology Spectrum Aug 2023is a genus of Gram-negative rods, which can cause persistent airway infections in people with cystic fibrosis (CF). The knowledge about virulence and clinical...
is a genus of Gram-negative rods, which can cause persistent airway infections in people with cystic fibrosis (CF). The knowledge about virulence and clinical implications of is still limited, and it is not fully established whether infections contribute to disease progression or if it is a marker of poor lung function. The most commonly reported species in CF is A. xylosoxidans. While other spp. are also identified in CF airways, the currently used Matrix-Assisted Laser Desorption/Ionization Time Of Flight Mass Spectrometry (MALDI-TOF MS) method in routine diagnostics cannot distinguish between species. Differences in virulence between species have consequently not been well studied. In this study, we compare phenotypes and proinflammatory properties of A. xylosoxidans, , , and using models. Bacterial supernatants were used to stimulate CF bronchial epithelial cells and whole blood from healthy individuals. Supernatants from the well-characterized CF-pathogen Pseudomonas aeruginosa were included for comparison. Inflammatory mediators were analyzed with ELISA and leukocyte activation was assessed using flow cytometry. The four species differed in morphology seen in scanning electron microscopy (SEM), but there were no observed differences in swimming motility or biofilm formation. Exoproducts from all species except caused significant IL-6 and IL-8 secretion from CF lung epithelium. The cytokine release was equivalent or stronger than the response induced by P. aeruginosa. All species activated neutrophils and monocytes in a lipopolysaccharide (LPS)-independent manner. Our results indicate that exoproducts of the four included species do not differ consistently in causing inflammatory responses, but they are equally or even more capable of inducing inflammation compared with the classical CF pathogen P. aeruginosa. Achromobacter xylosoxidans is an emerging pathogen among people with cystic fibrosis (CF). Current routine diagnostic methods are often unable to distinguish A. xylosoxidans from other species, and the clinical relevance of different species is still unknown. In this work, we show that four different species relevant to CF evoke similar inflammatory responses from airway epithelium and leukocytes , but they are all equally or even more proinflammatory compared to the classic CF-pathogen Pseudomonas aeruginosa. The results suggest that species are important airway pathogens in CF, and that all species are relevant to treat.
Topics: Humans; Achromobacter; Cystic Fibrosis; Gram-Negative Bacterial Infections; Achromobacter denitrificans; Lung
PubMed: 37284754
DOI: 10.1128/spectrum.00195-23