Failed Eradication Therapy of New-Onset Pseudomonas Aeruginosa Infections in Children With Cystic Fibrosis Is Associated With Bacterial Resistance to Neutrophil Functions

Overview

Journal J Infect Dis

Publisher Oxford University Press

Specialty Infectious Diseases

Date 2021 Feb 19

PMID 33606875

Citations 3

Authors

Kelly Kwong

Andrea Benedetti

Yvonne Yau

Valerie Waters

Dao Nguyen

Affiliations

Soon will be listed here.

Abstract

Background: Antibiotics, such as inhaled tobramycin, are used to eradicate new-onset Pseudomonas aeruginosa (PA) infections in patients with cystic fibrosis (CF) but frequently fail due to reasons poorly understood. We hypothesized that PA isolates' resistance to neutrophil antibacterial functions was associated with failed eradication in patients harboring those strains.

Methods: We analyzed all PA isolates from a cohort of 39 CF children with new-onset PA infections undergoing tobramycin eradication therapy, where 30 patients had eradicated and 9 patients had persistent infection. We characterized several bacterial phenotypes and measured the isolates' susceptibility to neutrophil antibacterial functions using in vitro assays of phagocytosis and intracellular bacterial killing.

Results: PA isolates from persistent infections were more resistant to neutrophil functions, with lower phagocytosis and intracellular bacterial killing compared to those from eradicated infections. In multivariable analyses, in vitro neutrophil responses were positively associated with twitching motility, and negatively with mucoidy. In vitro neutrophil phagocytosis was a predictor of persistent infection following tobramycin even after adjustment for clinical risk factors.

Conclusions: PA isolates from new-onset CF infection show strain-specific susceptibility to neutrophil antibacterial functions, and infection with PA isolates resistant to neutrophil phagocytosis is an independent risk factor for failed tobramycin eradication.

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References

Ratner D, Mueller C . Immune responses in cystic fibrosis: are they intrinsically defective?. Am J Respir Cell Mol Biol. 2012; 46(6):715-22. DOI: 10.1165/rcmb.2011-0399RT. View

Mahenthiralingam E, CAMPBELL M, Speert D . Nonmotility and phagocytic resistance of Pseudomonas aeruginosa isolates from chronically colonized patients with cystic fibrosis. Infect Immun. 1994; 62(2):596-605. PMC: 186146. DOI: 10.1128/iai.62.2.596-605.1994. View

Vidya P, Smith L, Beaudoin T, Yau Y, Clark S, Coburn B . Chronic infection phenotypes of Pseudomonas aeruginosa are associated with failure of eradication in children with cystic fibrosis. Eur J Clin Microbiol Infect Dis. 2015; 35(1):67-74. DOI: 10.1007/s10096-015-2509-4. View

Painter R, Valentine V, Lanson Jr N, Leidal K, Zhang Q, Lombard G . CFTR Expression in human neutrophils and the phagolysosomal chlorination defect in cystic fibrosis. Biochemistry. 2006; 45(34):10260-9. PMC: 2931333. DOI: 10.1021/bi060490t. View

Pestrak M, Chaney S, Eggleston H, Dellos-Nolan S, Dixit S, Mathew-Steiner S . Pseudomonas aeruginosa rugose small-colony variants evade host clearance, are hyper-inflammatory, and persist in multiple host environments. PLoS Pathog. 2018; 14(2):e1006842. PMC: 5812653. DOI: 10.1371/journal.ppat.1006842. View

Marvig R, Sommer L, Molin S, Krogh Johansen H . Convergent evolution and adaptation of Pseudomonas aeruginosa within patients with cystic fibrosis. Nat Genet. 2014; 47(1):57-64. DOI: 10.1038/ng.3148. View

Young R, Malcolm K, Kret J, Caceres S, Poch K, Nichols D . Neutrophil extracellular trap (NET)-mediated killing of Pseudomonas aeruginosa: evidence of acquired resistance within the CF airway, independent of CFTR. PLoS One. 2011; 6(9):e23637. PMC: 3164657. DOI: 10.1371/journal.pone.0023637. View

SenGupta S, Hittle L, Ernst R, Uriarte S, Mitchell T . A Pseudomonas aeruginosa hepta-acylated lipid A variant associated with cystic fibrosis selectively activates human neutrophils. J Leukoc Biol. 2016; 100(5):1047-1059. PMC: 6608067. DOI: 10.1189/jlb.4VMA0316-101R. View

Kosorok M, Jalaluddin M, Farrell P, Shen G, Colby C, Laxova A . Comprehensive analysis of risk factors for acquisition of Pseudomonas aeruginosa in young children with cystic fibrosis. Pediatr Pulmonol. 1998; 26(2):81-8. DOI: 10.1002/(sici)1099-0496(199808)26:2<81::aid-ppul2>3.0.co;2-k. View

10.

Speert D, Eftekhar F, Puterman M . Nonopsonic phagocytosis of strains of Pseudomonas aeruginosa from cystic fibrosis patients. Infect Immun. 1984; 43(3):1006-11. PMC: 264285. DOI: 10.1128/iai.43.3.1006-1011.1984. View

11.

Gibson R, Burns J, Ramsey B . Pathophysiology and management of pulmonary infections in cystic fibrosis. Am J Respir Crit Care Med. 2003; 168(8):918-51. DOI: 10.1164/rccm.200304-505SO. View

12.

Hartl D, Gaggar A, Bruscia E, Hector A, Marcos V, Jung A . Innate immunity in cystic fibrosis lung disease. J Cyst Fibros. 2012; 11(5):363-82. DOI: 10.1016/j.jcf.2012.07.003. View

13.

Smith E, Buckley D, Wu Z, Saenphimmachak C, Hoffman L, DArgenio D . Genetic adaptation by Pseudomonas aeruginosa to the airways of cystic fibrosis patients. Proc Natl Acad Sci U S A. 2006; 103(22):8487-92. PMC: 1482519. DOI: 10.1073/pnas.0602138103. View

14.

Floyd M, Winn M, Cullen C, Sil P, Chassaing B, Yoo D . Swimming Motility Mediates the Formation of Neutrophil Extracellular Traps Induced by Flagellated Pseudomonas aeruginosa. PLoS Pathog. 2016; 12(11):e1005987. PMC: 5113990. DOI: 10.1371/journal.ppat.1005987. View

15.

Mayer-Hamblett N, Ramsey B, Kulasekara H, Wolter D, Houston L, Pope C . Pseudomonas aeruginosa phenotypes associated with eradication failure in children with cystic fibrosis. Clin Infect Dis. 2014; 59(5):624-31. PMC: 4148602. DOI: 10.1093/cid/ciu385. View

16.

Mishra M, Byrd M, Sergeant S, Azad A, Parsek M, McPhail L . Pseudomonas aeruginosa Psl polysaccharide reduces neutrophil phagocytosis and the oxidative response by limiting complement-mediated opsonization. Cell Microbiol. 2011; 14(1):95-106. PMC: 4466118. DOI: 10.1111/j.1462-5822.2011.01704.x. View

17.

Kelly N, Kluftinger J, Pasloske B, Paranchych W, Hancock R . Pseudomonas aeruginosa pili as ligands for nonopsonic phagocytosis by fibronectin-stimulated macrophages. Infect Immun. 1989; 57(12):3841-5. PMC: 259914. DOI: 10.1128/iai.57.12.3841-3845.1989. View

18.

Tramper-Stranders G, van der Ent C, Molin S, Yang L, Hansen S, Rau M . Initial Pseudomonas aeruginosa infection in patients with cystic fibrosis: characteristics of eradicated and persistent isolates. Clin Microbiol Infect. 2011; 18(6):567-74. DOI: 10.1111/j.1469-0691.2011.03627.x. View

19.

Kolaczkowska E, Kubes P . Neutrophil recruitment and function in health and inflammation. Nat Rev Immunol. 2013; 13(3):159-75. DOI: 10.1038/nri3399. View

20.

Treggiari M, Retsch-Bogart G, Mayer-Hamblett N, Khan U, Kulich M, Kronmal R . Comparative efficacy and safety of 4 randomized regimens to treat early Pseudomonas aeruginosa infection in children with cystic fibrosis. Arch Pediatr Adolesc Med. 2011; 165(9):847-56. PMC: 3991697. DOI: 10.1001/archpediatrics.2011.136. View