scholarly journals Cystic Fibrosis Sputum Impairs the Ability of Neutrophils to Kill Staphylococcus aureus

Pathogens ◽  
2021 ◽  
Vol 10 (6) ◽  
pp. 703
Author(s):  
Kayla Fantone ◽  
Samantha L. Tucker ◽  
Arthur Miller ◽  
Ruchi Yadav ◽  
Eryn E. Bernardy ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Staphylococcus Aureus ◽  
Healthy Volunteers ◽  
Airway Disease ◽  
Neutrophil Extracellular Trap ◽  
Lung Function Decline ◽  
Bacterial Killing ◽  
Cystic Fibrosis Sputum ◽  
Microbial Infections

Cystic fibrosis (CF) airway disease is characterized by chronic microbial infections and infiltration of inflammatory polymorphonuclear (PMN) granulocytes. Staphylococcus aureus (S. aureus) is a major lung pathogen in CF that persists despite the presence of PMNs and has been associated with CF lung function decline. While PMNs represent the main mechanism of the immune system to kill S. aureus, it remains largely unknown why PMNs fail to eliminate S. aureus in CF. The goal of this study was to observe how the CF airway environment affects S. aureus killing by PMNs. PMNs were isolated from the blood of healthy volunteers and CF patients. Clinical isolates of S. aureus were obtained from the airways of CF patients. The results show that PMNs from healthy volunteers were able to kill all CF isolates and laboratory strains of S. aureus tested in vitro. The extent of killing varied among strains. When PMNs were pretreated with supernatants of CF sputum, S. aureus killing was significantly inhibited suggesting that the CF airway environment compromises PMN antibacterial functions. CF blood PMNs were capable of killing S. aureus. Although bacterial killing was inhibited with CF sputum, PMN binding and phagocytosis of S. aureus was not diminished. The S. aureus-induced respiratory burst and neutrophil extracellular trap release from PMNs also remained uninhibited by CF sputum. In summary, our data demonstrate that the CF airway environment limits killing of S. aureus by PMNs and provides a new in vitro experimental model to study this phenomenon and its mechanism.

scholarly journals Functional and Transcriptional Adaptations of Blood Monocytes Recruited to the Cystic Fibrosis Airway Microenvironment In Vitro

2021 ◽  
Vol 22 (5) ◽  
pp. 2530
Author(s):  
Bijean D. Ford ◽  
Diego Moncada Giraldo ◽  
Camilla Margaroli ◽  
Vincent D. Giacalone ◽  
Milton R. Brown ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Bactericidal Activity ◽  
Scavenger Receptor ◽  
Receptor Expression ◽  
Blood Monocytes ◽  
Bacterial Killing ◽  
Blood Neutrophils ◽  
Vitro Model

Cystic fibrosis (CF) lung disease is dominated by the recruitment of myeloid cells (neutrophils and monocytes) from the blood which fail to clear the lung of colonizing microbes. In prior in vitro studies, we showed that blood neutrophils migrated through the well-differentiated lung epithelium into the CF airway fluid supernatant (ASN) mimic the dysfunction of CF airway neutrophils in vivo, including decreased bactericidal activity despite an increased metabolism. Here, we hypothesized that, in a similar manner to neutrophils, blood monocytes undergo significant adaptations upon recruitment to CFASN. To test this hypothesis, primary human blood monocytes were transmigrated in our in vitro model into the ASN from healthy control (HC) or CF subjects to mimic in vivo recruitment to normal or CF airways, respectively. Surface phenotype, metabolic and bacterial killing activities, and transcriptomic profile by RNA sequencing were quantified post-transmigration. Unlike neutrophils, monocytes were not metabolically activated, nor did they show broad differences in activation and scavenger receptor expression upon recruitment to the CFASN compared to HCASN. However, monocytes recruited to CFASN showed decreased bactericidal activity. RNASeq analysis showed strong effects of transmigration on monocyte RNA profile, with differences between CFASN and HCASN conditions, notably in immune signaling, including lower expression in the former of the antimicrobial factor ISG15, defensin-like chemokine CXCL11, and nitric oxide-producing enzyme NOS3. While monocytes undergo qualitatively different adaptations from those seen in neutrophils upon recruitment to the CF airway microenvironment, their bactericidal activity is also dysregulated, which could explain why they also fail to protect CF airways from infection.

scholarly journals Activity of Gatifloxacin in an In Vitro Pharmacokinetic-Pharmacodynamic Model against Staphylococcus aureus Strains either Susceptible to Ciprofloxacin or Exhibiting Various Levels and Mechanisms of Ciprofloxacin Resistance

2006 ◽  
Vol 50 (6) ◽  
pp. 1931-1936 ◽  
Author(s):  
Boubakar B. Ba ◽  
Corinne Arpin ◽  
Céline Vidaillac ◽  
Arnaud Chausse ◽  
Marie-Claude Saux ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Goodness Of Fit ◽  
Reference Strain ◽  
Pharmacodynamic Model ◽  
Bacterial Killing ◽  
Β Phase ◽  
Ciprofloxacin Resistance ◽  
Total Elimination ◽  
Gram Positive Cocci

ABSTRACT Gatifloxacin (GAT) is a new 8-methoxy fluoroquinolone with enhanced activity against gram-positive cocci. Its activity was studied in an in vitro pharmacokinetic-pharmacodynamic model against five Staphylococcus aureus strains, either susceptible to ciprofloxacin or exhibiting various levels and mechanisms of ciprofloxacin (CIP) resistance: the ATCC 25923 reference strain (MICs of CIP and GAT: 0.5 and 0.1 μg/ml, respectively), its efflux mutant SA-1 (16 and 0.5 μg/ml; mutation in the norA promoter region), and three clinical strains, Sa2102 (2 and 0.2 μg/ml), Sa2667 (4 and 0.5 μg/ml), and Sa2669 (16 and 1 μg/ml), carrying mutations in the grlA (Ser80Tyr or Phe) and gyrA (Ser84Ala) quinolone resistance-determining regions (QRDRs) for Sa2669. Plasmatic pharmacokinetic profiles after daily 1-h perfusion of 400 mg for 48 h were accurately simulated. Thus, mean maximum concentration of drug in serum values for the two administration intervals were 5.36 and 5.80 μg/ml, respectively, and the corresponding half-life at β-phase values were 8.68 and 7.80 h (goodness of fit coefficient, >0.98). Therapeutic concentrations of GAT allowed the complete eradication of the susceptible strain within 12 h (difference between the bacterial counts at the beginning of the treatment and at a defined time: −2.18 at the 1-h time point [t 1] and −6.80 at t 24 and t 48; the bacterial killing and regrowth curve from 0 to 48 h was 30.2 h × log CFU/milliliter). However, mutants (M) with GAT MICs increased by 4- to 40-fold were selected from the other strains. They acquired mutations either supplementary (MSa2102 and MSa2667) or different (Ala84Val for MSa2669) in gyrA or in both gyrA and grlA QRDRs (MSA-1). MSa2667 additionally overproduced efflux system(s) without norA promoter modification. Thus, GAT properties should allow the total elimination of ciprofloxacin-susceptible S. aureus, but resistant mutants might emerge from strains showing reduced susceptibility to older fluoroquinolones independently of the first-step mutation(s).

PHAGE GROUPS AND ANTIBIOTIC SENSITIVITY OF STAPHYLOCOCCUS AUREUS ASSOCIATED WITH CYSTIC FIBROSIS OF THE PANCREAS

PEDIATRICS ◽  
1959 ◽  
Vol 24 (1) ◽  
pp. 40-42
Author(s):  
Fred E. Pittman ◽  
Calderon Howe ◽  
Louise Goode ◽  
Paul A. di Sant'Agnese
Keyword(s):  
Cystic Fibrosis ◽  
Staphylococcus Aureus ◽  
Phage Type ◽  
Antibiotic Sensitivity ◽  
Phage Group ◽  
Staph Aureus ◽  
Group Iii

In this study, 198 strains of hemolytic, coagulase-positive Staph. aureus were recovered from 84 patients with cystic fibrosis of the pancreas and some of their relatives. The majority of the organisms fell into phage group III and were resistant in vitro to penicillin and other antibiotics. No single phage type seemed to be unduly prevalent in this group of patients with cystic fibrosis of the pancreas.

scholarly journals Most of Staphylococcus aureus and Pseudomonas aeruginosa co-infecting isolates coexist, a condition that may impact clinical outcomes in Cystic Fibrosis patients

2020 ◽  
Author(s):  
Paul Briaud ◽  
Sylvère Bastien ◽  
Laura Camus ◽  
Marie Boyadjian ◽  
Philippe Reix ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Staphylococcus Aureus ◽  
Pseudomonas Aeruginosa ◽  
Multivariate Analysis ◽  
Natural History ◽  
Clinical Outcomes ◽  
Bacterial Colonization ◽  
Childhood And Adolescence ◽  
History Of

AbstractStaphylococcus aureus (SA) is the major colonizer of the lung of cystic fibrosis (CF) patient during childhood and adolescence. As patient aged, the prevalence of SA decreases and Pseudomonas aeruginosa (PA) becomes the major pathogen infecting adult lungs. Nonetheless, SA remains significant and patients harbouring both SA and PA are frequently found in worldwide cohort. Impact of coinfection remains controversial. Furthermore, co-infecting isolates may compete or coexist. The aim of this study was to analyse if co-infection and coexistence of SA and PA could lead to worse clinical outcomes. The clinical and bacteriological data of 212 Lyon CF patients were collected retrospectively, and patients were ranked into three groups, SA only (n=112), PA only (n=48) or SA plus PA (n=52). In addition, SA and PA isolates from co-infecting patients were tested in vitro to define their interaction profile. Sixty five percent (n=34) of SA/PA pairs coexist. Using univariate and multivariate analysis, we confirm that SA patients have a clinical condition less severe than others, and PA induce a poor outcome independently of the presence of SA. FEV1 is lower in patients infected by competition strain pairs than in those infected by coexisting strain pairs compared to SA mono-infection. Coexistence between SA and PA may be an important step in the natural history of lung bacterial colonization within CF patients.

scholarly journals Activity of Telavancin against Staphylococcus aureus Isolates, Including Those with Decreased Susceptibility to Ceftaroline, from Cystic Fibrosis Patients

2018 ◽  
Vol 62 (9) ◽  
Author(s):  
Melanie Roch ◽  
Maria Celeste Varela ◽  
Agustina Taglialegna ◽  
Warren E. Rose ◽  
Adriana E. Rosato
Keyword(s):  
Cystic Fibrosis ◽  
Staphylococcus Aureus ◽  
Galleria Mellonella ◽  
Therapeutic Option ◽  
The United States ◽  
Infection Model ◽  
Content Type ◽  
Complicated Skin ◽  
Hospital Acquired

ABSTRACT Methicillin-resistant Staphylococcus aureus (MRSA) acquisition in cystic fibrosis (CF) patients confers a clinical outcome worse than that in non-CF patients with an increased rate of declined lung function. Telavancin, an approved lipoglycopeptide used to treat infections due to S. aureus, has a dual mode of action causing inhibition of peptidoglycan synthesis and membrane depolarization. MRSA infections in CF patients remain an important problem with no foreseeable decline in prevalence rates. Although telavancin is currently in clinical use for the treatment of complicated skin infections and hospital-acquired pneumonia, the activity against S. aureus infections in CF patients has not been investigated. In this work, we studied the activity of telavancin against CF patient-derived S. aureus strains collected from geographically diverse CF centers in the United States. We found that the telavancin MIC90 was 0.06 μg/ml, 8-fold lower than the ceftaroline or daptomycin MIC90 and 25-fold lower than the linezolid and vancomycin MIC90. We demonstrate that telavancin at serum free concentrations has rapid bactericidal activity, with a decrease of more than 3 log10 CFU/ml being achieved during the first 4 to 6 h of treatment, performing better in this assay than vancomycin and ceftaroline, including against S. aureus strains resistant to ceftaroline. Telavancin resistance was infrequent (0.3%), although we found that it can occur in vitro in both CF- and non-CF patient-derived S. aureus strains by progressive passages with subinhibitory concentrations. Genetic analysis of telavancin-resistant in vitro mutants showed gene polymorphisms in cell wall and virulence genes and increased survival in a Galleria mellonella infection model. Thus, we conclude that telavancin represents a promising therapeutic option for infections in CF patients with potent in vitro activity and a low resistance development potential.

scholarly journals Characterization of a Novel Bacteriophage Henu2 and Evaluation of the Synergistic Antibacterial Activity of Phage-Antibiotics

Antibiotics ◽  
2021 ◽  
Vol 10 (2) ◽  
pp. 174
Author(s):  
Xianghui Li ◽  
Tongxin Hu ◽  
Jiacun Wei ◽  
Yuhua He ◽  
Abualgasim Elgaili Abdalla ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Burst Size ◽  
Open Reading Frames ◽  
Comparative Genomic ◽  
Sewage Sample ◽  
Bacterial Killing ◽  
Wide Range ◽  
The Family ◽  
Infected Cells

Staphylococcus aureus phage Henu2 was isolated from a sewage sample collected in Kaifeng, China, in 2017. In this study, Henu2, a linear double-stranded DNA virus, was sequenced and found to be 43,513 bp long with 35% G + C content and 63 putative open reading frames (ORFs). Phage Henu2 belongs to the family Siphoviridae and possesses an isometric head (63 nm in diameter). The latent time and burst size of Henu2 were approximately 20 min and 7.8 plaque forming unit (PFU)/infected cells. The Henu2 maintained infectivity over a wide range of temperature (10–60 °C) and pH values (4–12). Phylogenetic and comparative genomic analyses indicate that Staphylococcus aureus phage Henu2 should be a new member of the family of Siphoviridae class-II. In this paper, Phage Henu2 alone exhibited weak inhibitory activity on the growth of S. aureus. However, the combination of phage Henu2 and some antibiotics or oxides could effectively inhibit the growth of S. aureus, with a decrease of more than three logs within 24 h in vitro. These results provide useful information that phage Henu2 can be combined with antibiotics to increase the production of phage Henu2 and thus enhance the efficacy of bacterial killing.

scholarly journals In VitroPharmacodynamics of Vancomycin and Cefazolin Alone and in Combination against Methicillin-Resistant Staphylococcus aureus

2011 ◽  
Vol 56 (1) ◽  
pp. 202-207 ◽  
Author(s):  
Mao Hagihara ◽  
Dora E. Wiskirchen ◽  
Joseph L. Kuti ◽  
David P. Nicolau
Keyword(s):  
Staphylococcus Aureus ◽  
Combination Therapy ◽  
Synergistic Effects ◽  
Bacterial Density ◽  
Bacterial Killing ◽  
Methicillin Resistant ◽  
Content Type ◽  
Vancomycin Mics ◽  
Time Kill

ABSTRACTPrevious studies employing time-kill methods have observed synergistic effects against methicillin-resistantStaphylococcus aureus(MRSA) when a β-lactam is combined with vancomycin. However, these time-kill studies have neglected the importance of human-simulated exposures. We evaluated the effect of human simulated exposures of vancomycin at 1 g every 8 h (q8h) in combination with cefazolin at 1 g q8h against various MRSA isolates. Four clinical isolates (two MRSA isolates [vancomycin MICs, 0.5 and 2.0 μg/ml], a heterogeneous vancomycin-intermediateS. aureus[hVISA] isolate [MIC, 2.0 μg/ml], and a vancomycin-intermediateS. aureus[VISA] isolate [MIC, 8.0 μg/ml]) were evaluated in anin vitropharmacodynamic model with a starting inoculum of 106or 108CFU/ml. Bacterial density was measured over 48 to 72 h. Time-kill curves were constructed, and the area under the bacterial killing and regrowth curve (AUBC) was calculated. During 106CFU/ml studies, combination therapy achieved greater log10CFU/ml changes than vancomycin alone at 12 h (−4.31 ± 0.58 versus −2.80 ± 0.59,P< 0.001), but not at 48 h. Combination therapy significantly reduced the AUBC from 0 to 48 h (122 ± 14) compared with vancomycin alone (148 ± 22,P= 0.017). Similar results were observed during 108CFU/ml studies, where combination therapy achieved greater log10CFU/ml changes at 12 h than vancomycin alone (−4.00 ± 0.20 versus −1.10 ± 0.04,P< 0.001) and significantly reduced the AUBC (275 ± 30 versus 429 ± 37,P< 0.001) after 72 h of incubation. In this study, the combination of vancomycin and cefazolin at human-simulated exposures improved the rate of kill against these MRSA isolates and resulted in greater overall antibacterial effect, but no differences in bacterial density were observed by the end of the experiments.

scholarly journals Cedecea davisae’s Role in a Polymicrobial Lung Infection in a Cystic Fibrosis Patient

2012 ◽  
Vol 2012 ◽  
pp. 1-4 ◽  
Author(s):  
Thayer G. Ismaael ◽  
Eleana M. Zamora ◽  
Faisal A. Khasawneh
Keyword(s):  
Cystic Fibrosis ◽  
Staphylococcus Aureus ◽  
Burkholderia Cepacia ◽  
Airway Disease ◽  
Lung Infection ◽  
Emerging Pathogen ◽  
The Family ◽  
Healthcare Associated ◽  
Airway Colonization

Chronic airway colonization and infection are the hallmark of cystic fibrosis (CF).Staphylococcus aureus, Pseudomonas aeruginosa, andBurkholderia cepaciaare well-documented bacterial culprits in this chronic suppurative airway disease. Advanced molecular diagnostics have uncovered a possible role of a larger group of microorganisms in CF.Cedeceais a member of the family Enterobacteriaceae and is an emerging pathogen. We present a case of a polymicrobial healthcare-associated pneumonia in a CF patient caused byCedecea davisae, among other bacteria.

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