Impact of the Epithelial Lining Fluid Milieu on Amikacin Pharmacodynamics Against Pseudomonas aeruginosa.
Journal
Drugs in R&D
ISSN: 1179-6901
Titre abrégé: Drugs R D
Pays: New Zealand
ID NLM: 100883647
Informations de publication
Date de publication:
Jun 2021
Jun 2021
Historique:
accepted:
18
03
2021
pubmed:
3
4
2021
medline:
26
10
2021
entrez:
2
4
2021
Statut:
ppublish
Résumé
Even though nebulised administration of amikacin can achieve high epithelial lining fluid concentrations, this has not translated into improved patient outcomes in clinical trials. One possible reason is that the cellular and chemical composition of the epithelial lining fluid may inhibit amikacin-mediated bacterial killing. The objective of this study was to identify whether the epithelial lining fluid components inhibit amikacin-mediated bacterial killing. Two amikacin-susceptible (minimum inhibitory concentrations of 2 and 8 mg/L) Pseudomonas aeruginosa isolates were exposed in vitro to amikacin concentrations up to 976 mg/L in the presence of an acidic pH, mucin and/or surfactant as a means of simulating the epithelial lining fluid, the site of bacterial infection in pneumonia. Pharmacodynamic modelling was used to describe associations between amikacin concentrations, bacterial killing and emergence of resistance. In the presence of broth alone, there was rapid and extensive (> 6 - log Our findings indicate that simulating the epithelial lining fluid antagonises amikacin-mediated killing of P. aeruginosa, even at the high concentrations achieved following nebulised administration.
Sections du résumé
BACKGROUND
BACKGROUND
Even though nebulised administration of amikacin can achieve high epithelial lining fluid concentrations, this has not translated into improved patient outcomes in clinical trials. One possible reason is that the cellular and chemical composition of the epithelial lining fluid may inhibit amikacin-mediated bacterial killing.
OBJECTIVE
OBJECTIVE
The objective of this study was to identify whether the epithelial lining fluid components inhibit amikacin-mediated bacterial killing.
METHODS
METHODS
Two amikacin-susceptible (minimum inhibitory concentrations of 2 and 8 mg/L) Pseudomonas aeruginosa isolates were exposed in vitro to amikacin concentrations up to 976 mg/L in the presence of an acidic pH, mucin and/or surfactant as a means of simulating the epithelial lining fluid, the site of bacterial infection in pneumonia. Pharmacodynamic modelling was used to describe associations between amikacin concentrations, bacterial killing and emergence of resistance.
RESULTS
RESULTS
In the presence of broth alone, there was rapid and extensive (> 6 - log
CONCLUSIONS
CONCLUSIONS
Our findings indicate that simulating the epithelial lining fluid antagonises amikacin-mediated killing of P. aeruginosa, even at the high concentrations achieved following nebulised administration.
Identifiants
pubmed: 33797739
doi: 10.1007/s40268-021-00344-5
pii: 10.1007/s40268-021-00344-5
pmc: PMC8017437
doi:
Substances chimiques
Anti-Bacterial Agents
0
Amikacin
84319SGC3C
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
203-215Références
Elliott D, Elliott R, Burrell A, Harrigan P, Murgo M, Rolls K, et al. Incidence of ventilator-associated pneumonia in Australasian intensive care units: use of a consensus-developed clinical surveillance checklist in a multisite prospective audit. BMJ Open. 2015;5:e008924.
pubmed: 26515685
pmcid: 4636654
Melsen WG, Rovers MM, Groenwold RHH, Bergmans D, Camus C, Bauer TT, et al. Attributable mortality of ventilator-associated pneumonia: a meta-analysis of individual patient data from randomised prevention studies. Lancet Infect Dis. 2013;13:665–71.
pubmed: 23622939
Scaglione F, Esposito S, Leone S, Lucini V, Pannacci M, Ma L, et al. Feedback dose alteration significantly affects probability of pathogen eradication in nosocomial pneumonia. Eur Respir J. 2009;34:394–400.
pubmed: 19213786
Nicasio AM, Eagye KJ, Nicolau DP, Shore E, Palter M, Pepe J, et al. Pharmacodynamic-based clinical pathway for empiric antibiotic choice in patients with ventilator-associated pneumonia. J Crit Care. 2010;25:69–77.
pubmed: 19427167
Kalil AC, Metersky ML, Klompas M, Muscedere J, Sweeney DA, Palmer LB, et al. Management of adults with hospital-acquired and ventilator-associated pneumonia: 2016 clinical practice guidelines by the Infectious Diseases Society of America and the American Thoracic Society. Clin Infect Dis. 2016;63:575–82.
pubmed: 27521441
pmcid: 4981763
Kiem S, Schentag JJ. Interpretation of antibiotic concentration ratios measured in epithelial lining fluid. Antimicrob Agents Chemother. 2008;52:24–36.
pubmed: 17846133
Najmeddin F, Shahrami B, Azadbakht S, Dianatkhah M, Rouini MR, Najafi A, et al. Evaluation of epithelial lining fluid concentration of amikacin in critically ill patients with ventilator-associated pneumonia. J Intensive Care Med. 2020;35(4):400–4.
pubmed: 29471721
Moore RD, Lietman PS, Smith CR. Clinical response to aminoglycoside therapy: importance of the ratio of peak concentration to minimal inhibitory concentration. J Infect Dis. 1987;155:93–9.
pubmed: 3540140
Kashuba ADM, Nafziger AN, Drusano GL, Bertino JS. Optimizing aminoglycoside therapy for nosocomial pneumonia caused by Gram-negative bacteria. Antimicrob Agents Chemother. 1999;43:623–9.
pubmed: 10049277
pmcid: 89170
Shortridge D, Gales AC, Streit JM, Huband MD, Tsakris A, Jones RN. Geographic and temporal patterns of antimicrobial resistance in Pseudomonas aeruginosa over 20 years from the SENTRY Antimicrobial Surveillance Program, 1997–2016. Open Forum Infect Dis. 2019;6(Suppl. 1):S63–8.
pubmed: 30895216
pmcid: 6419917
Weiner LM, Webb AK, Limbago B, Dudeck MA, Patel J, Kallen AJ, et al. Antimicrobial-resistant pathogens associated with healthcare-associated infections: summary of data reported to the National Healthcare Safety Network at the Centers for Disease Control and Prevention, 2011–2014. Infect Control Hosp Epidemiol. 2016;37:1288–301.
pubmed: 27573805
pmcid: 6857725
Roger C, Nucci B, Louart B, Friggeri A, Knani H, Evrard A, et al. Impact of 30 mg/kg amikacin and 8 mg/kg gentamicin on serum concentrations in critically ill patients with severe sepsis. J Antimicrob Chemother. 2016;71:208–12.
pubmed: 26429564
Roger C, Nucci B, Molinari N, Bastide S, Saissi G, Pradel G, et al. Standard dosing of amikacin and gentamicin in critically ill patients results in variable and subtherapeutic concentrations. Int J Antimicrob Agents. 2015;46:21–7.
pubmed: 25857948
Luyt CE, Clavel M, Guntupalli K, Johannigman J, Kennedy JI, Wood C, et al. Pharmacokinetics and lung delivery of PDDS-aerosolized amikacin (NKTR-061) in intubated and mechanically ventilated patients with nosocomial pneumonia. Crit Care. 2009;13:R200.
pubmed: 20003269
pmcid: 2811890
Kollef MH, Ricard JD, Roux D, Francois B, Ischaki E, Rozgonyi Z, et al. A randomized trial of the amikacin fosfomycin inhalation system for the adjunctive therapy of Gram-negative ventilator-associated pneumonia IASIS trial. Chest. 2017;151:1239–46.
pubmed: 27890714
Rello J, Sole-Lleonart C, Rouby JJ, Chastre J, Blot S, Poulakou G, et al. Use of nebulized antimicrobials for the treatment of respiratory infections in invasively mechanically ventilated adults: a position paper from the European Society of Clinical Microbiology and Infectious Diseases. Clin Microbiol Infect Dis. 2017;23:629–39.
Niederman MS, Alder J, Bassetti M, et al. Inhaled amikacin adjunctive to intravenous standard-of-care antibiotics in mechanically ventilated patients with Gram-negative pneumonia (INHALE): a double-blind, randomised, placebo-controlled, phase 3, superiority trial. Lancet Infect Dis. 2020;20:330–40.
pubmed: 31866328
Leconte P, Potel G, Peltier P, Horeau D, Caillon J, Juvin ME, et al. Lung distribution and pharmacokinetics of aerosolized tobramycin. Am Rev Respir Dis. 1993;147:1279–82.
Elman M, Goldstein I, Marquette CH, Wallet F, Lenaour G, Rouby JJ, et al. Influence of lung aeration on pulmonary concentrations of nebulized and intravenous amikacin in ventilated piglets with severe bronchopneumonia. Anesthesiology. 2002;97:199–206.
pubmed: 12131123
Rouby JJ, Monsel A, Ehrmann S, Bouglé A, Laterre PF. The INHALE trial: multiple reasons for a negative result. Lancet Infect Dis. 2020;20(7):778–9.
pubmed: 32592666
Bataillon V, Lhermitte M, Lafitte JJ, Pommery J, Roussel P. The binding of amikacin to macromolecules from the sputum of patients suffering from respiratory diseases. J Antimicrob Chemother. 1992;29:499–508.
pubmed: 1624390
Huang JX, Blaskovich MA, Pelingon R, Ramu S, Kavanagh A, Elliott AG, et al. Mucin binding reduces colistin antimicrobial activity. Antimicrob Agents Chemother. 2015;59:5925–31.
pubmed: 26169405
pmcid: 4576126
van’t Veen A, Mouton JW, Gommers D, Kluytmans JA, Dekkers P, Lachmann B. Influence of pulmonary surfactant on in vitro bactericidal activities of amoxicillin, ceftazidime, and tobramycin. Antimicrob Agents Chemother. 1995;39:329–33.
Bodem CR, Lampton LM, Miller DP, Tarka EF, Everett ED. Endobronchial pH. Relevance of aminoglycoside activity in Gram-negative bacillary pneumonia. Am Rev Respir Dis. 1983;127:39–41.
pubmed: 6849547
Kim KC. Role of epithelial mucins during airway infection. Pulm Pharmacol Ther. 2012;25:415–9.
pubmed: 22198062
Schlessinger D. Failure of aminoglycoside antibiotics to kill anaerobic, low-pH, and resistant cultures. Clin Microbiol Rev. 1988;1:54–9.
pubmed: 3060245
pmcid: 358029
Wiegand I, Hilpert K, Hancock RE. Agar and broth dilution methods to determine the minimal inhibitory concentration (MIC) of antimicrobial substances. Nat Protoc. 2008;3:163–75.
pubmed: 18274517
Hasselmann C, European Soc Clinical M. Determination of minimum inhibitory concentrations (MICs) of antibacterial agents by broth dilution. Clin Microbiol Infect. 2003;9:7.
Drusano GL, Liu W, Fikes S, Cirz R, Robbins N, Kurhanewicz S, et al. Interaction of drug- and granulocyte-mediated killing of Pseudomonas aeruginosa in a murine pneumonia model. J Infect Dis. 2014;210:1319–24.
pubmed: 24760199
pmcid: 4271070
Hunt BE, Weber A, Berger A, Ramsey B, Smith AL. Macromolecular mechanisms of sputum inhibition of tobramycin activity. Antimicrob Agents Chemother. 1995;39:34–9.
pubmed: 7535039
pmcid: 162480
Raymondos K, Leuwer M, Haslam PL, Vangerow B, Ensink M, Tschorn H, et al. Compositional, structural, and functional alterations in pulmonary surfactant in surgical patients after the early onset of systemic inflammatory response syndrome or sepsis. Crit Care Med. 1999;27:82–9.
pubmed: 9934898
Neely MN, van Guilder MG, Yamada WM, Schumitzky A, Jelliffe RW. Accurate detection of outliers and subpopulations with Pmetrics, a nonparametric and parametric pharmacometric modeling and simulation package for R. Ther Drug Monit. 2012;34:467–76.
pubmed: 22722776
pmcid: 3394880
Gumbo T, Louie A, Deziel MR, Parsons LM, Salfinger M, Drusano GL. Selection of a moxifloxacin dose that suppresses drug resistance in Mycobacterium tuberculosis, by use of an in vitro pharmacodynamic infection model and mathematical modeling. J Infect Dis. 2004;190:1642–51.
pubmed: 15478070
Landry RM, An D, Hupp JT, Singh PK, Parsek MR. Mucin–Pseudomonas aeruginosa interactions promote biofilm formation and antibiotic resistance. Mol Microbiol. 2006;59:142–51.
pubmed: 16359324
Co JY, Cárcamo-Oyarce G, Billings N, Wheeler KM, Grindy SC, Holten-Andersen N, et al. Mucins trigger dispersal of Pseudomonas aeruginosa biofilms. NPJ Biofilms Microbiomes. 2018;4:23. https://doi.org/10.1038/s41522-018-0067-0 .
doi: 10.1038/s41522-018-0067-0
pubmed: 30323945
pmcid: 6180003
Sun E, Gill EE, Falsafi R, Yeung A, Liu SJ, Hancock REW. Broad-spectrum adaptive antibiotic resistance associated with Pseudomonas aeruginosa mucin-dependent surfing motility. Antimicrob Agents Chemother. 2018;62(9):e00848-e918. https://doi.org/10.1128/AAC.00848-18 .
doi: 10.1128/AAC.00848-18
pubmed: 29967020
pmcid: 6125533
Lebeaux D, Chauhan A, Letoffe S, Fischer F, de Reuse H, Beloin C, et al. pH-mediated potentiation of aminoglycosides kills bacterial persisters and eradicates in vivo biofilms. J Infect Dis. 2014;210:1357–66.
pubmed: 24837402
Shields RK, Clancy CJ, Press EG, Nguyen MH. Aminoglycosides for treatment of bacteremia due to carbapenem-resistant Klebsiella pneumoniae. Antimicrob Agents Chemother. 2016;60:3187–92.
pubmed: 26926642
pmcid: 4862490
Vidal L, Gafter-Gvili A, Borok S, Fraser A, Leibovici L, Paul M. Efficacy and safety of aminoglycoside monotherapy: systematic review and meta-analysis of randomized controlled trials. J Antimicrob Chemother. 2007;60:247–57.
pubmed: 17562680
Powell J, Garnett JP, Mather MW, Cooles FAH, Nelson A, Verdon B, et al. Excess mucin impairs subglottic epithelial host defense in mechanically ventilated patients. Am J Respir Crit Care Med. 2018;198:340–9.
pubmed: 29425465
Planquette B, Timsit JF, Misset BY, Schwebel C, Azoulay E, Adrie C, et al. Pseudomonas aeruginosa ventilator-associated pneumonia predictive factors of treatment failure. Am J Respir Crit Care Med. 2013;188:69–76.
pubmed: 23641973
Rees VE, Bulitta JB, Oliver A, Tsuji BT, Rayner CR, Nation RL, et al. Resistance suppression by high-intensity, short-duration aminoglycoside exposure against hypermutable and non-hypermutable Pseudomonas aeruginosa. J Antimicrob Chemother. 2016;71:3157–67.
pubmed: 27521357
pmcid: 5079302
Padra M, Adamczyk B, Benktander J, Flahou B, Skoog EC, Padra JT, et al. Helicobacter suis binding to carbohydrates on human and porcine gastric mucins and glycolipids occurs via two modes. Virulence. 2018;9:898–918.
pubmed: 29638186
pmcid: 5955484
Karlsson NG, Nordman H, Karlsson H, Carlstedt I, Hansson GC. Glycosylation differences between pig gastric mucin populations: a comparative study of the neutral oligosaccharides using mass spectrometry. Biochem J. 1997;326:911–7.
pubmed: 9307045
pmcid: 1218750
Perez-Vilar J, Hill RL. The structure and assembly of secreted mucins. J Biol Chem. 1999;274:31751–4.
pubmed: 10542193
Wiseman LR, Bryson HM. Porcine-derived lung surfactant. A review of the therapeutic efficacy and clinical tolerability of a natural surfactant preparation (Curosurf) in neonatal respiratory distress syndrome. Drugs. 1994;48:386–403.
pubmed: 7527760