1887

Abstract

is an emerging pulmonary pathogen with limited treatment options. Nitric oxide (NO) demonstrates antibacterial activity against various bacterial species, including mycobacteria. In this study, we evaluated the effect of adjunctive inhaled NO therapy, using a novel NO generator, in a CF patient with pulmonary disease, and examined heterogeneity of response to NO .

In the compassionate-use treatment, a 24-year-old CF patient with pulmonary was treated with two courses of adjunctive intermittent NO, first at 160 p.p.m. for 21 days and subsequently by escalating the dose up to 240 p.p.m. for 8 days. Methemoglobin, pulmonary function, 6 min walk distance (6MWD), qualify of life and sputum microbiology were assessed. susceptibility tests were performed against patient’s isolate and comparison clinical isolates and quantified by Hill’s slopes calculated from time–kill curves.

lung infection eradication was not achieved, but improvements in selected qualify of life domains, lung function and 6MWD were observed during the study. Inhaled NO was well tolerated at 160 p.p.m. Dosing at 240 p.p.m. was stopped due to adverse symptoms, although methemoglobin levels remained within safety thresholds. susceptibility tests showed a dose-dependent NO effect on susceptibility and significant heterogeneity in response between clinical isolates. The patient’s isolate was found to be the least susceptible strain .

These results demonstrate heterogeneity in susceptibility to NO and suggest that longer treatment regimens could be required to see the reduction or eradication of more resistant pulmonary strains.

Funding
This study was supported by the:
  • Adrian M Zelazny , NIH Clinical Center , (Award 1ZIACL080013-11)
  • Kenneth N. Olivier , National Heart, Lung, and Blood Institute , (Award 1ZIAHL006200-04)
Loading

Article metrics loading...

/content/journal/acmi/10.1099/acmi.0.000154
2020-08-10
2020-10-22
Loading full text...

Full text loading...

/deliver/fulltext/acmi/2/9/acmi000154.html?itemId=/content/journal/acmi/10.1099/acmi.0.000154&mimeType=html&fmt=ahah

References

  1. Winthrop KL, McNelley E, Kendall B, Marshall-Olson A, Morris C et al. Pulmonary nontuberculous mycobacterial disease prevalence and clinical features: an emerging public health disease. Am J Respir Crit Care Med 2010; 182:977–982 [CrossRef][PubMed]
    [Google Scholar]
  2. Floto RA, Olivier KN, Saiman L, Daley CL, Herrmann J-L et al. Us cystic fibrosis Foundation and European cystic fibrosis Society consensus recommendations for the management of non-tuberculous mycobacteria in individuals with cystic fibrosis: Executive summary. Thorax 2016; 71:88–90 [CrossRef][PubMed]
    [Google Scholar]
  3. Griffith DE, Aksamit TR. Understanding nontuberculous mycobacterial lung disease: it's been a long time coming. F1000Res 2016; 5:2797 [CrossRef][PubMed]
    [Google Scholar]
  4. Döring G, Flume P, Heijerman H, Elborn JS. Consensus Study Group Treatment of lung infection in patients with cystic fibrosis: current and future strategies. J Cyst Fibros 2012; 11:461–479 [CrossRef][PubMed]
    [Google Scholar]
  5. Bogdan C. Nitric oxide and the immune response. Nat Immunol 2001; 2:907–916 [CrossRef][PubMed]
    [Google Scholar]
  6. Fang FC. Antimicrobial reactive oxygen and nitrogen species: concepts and controversies. Nat Rev Microbiol 2004; 2:820–832 [CrossRef][PubMed]
    [Google Scholar]
  7. Förstermann U, Sessa WC. Nitric oxide synthases: regulation and function. Eur Heart J 2012; 33:829–837 [CrossRef][PubMed]
    [Google Scholar]
  8. Jamaati H, Mortaz E, Pajouhi Z, Folkerts G, Movassaghi M et al. Nitric oxide in the pathogenesis and treatment of tuberculosis. Front Microbiol 2017; 8:8 [CrossRef][PubMed]
    [Google Scholar]
  9. Lee SC, Dickson DW, Liu W, Brosnan CF. Induction of nitric oxide synthase activity in human astrocytes by interleukin-1 beta and interferon-gamma. J Neuroimmunol 1993; 46:19–24 [CrossRef][PubMed]
    [Google Scholar]
  10. Wang CH, Lin HC, Liu CY, Huang KH, Huang TT et al. Upregulation of inducible nitric oxide synthase and cytokine secretion in peripheral blood monocytes from pulmonary tuberculosis patients. Int J Tuberc Lung Dis 2001; 5:283–291[PubMed]
    [Google Scholar]
  11. Flynn JL, Scanga CA, Tanaka KE, Chan J. Effects of aminoguanidine on latent murine tuberculosis. J Immunol 1998; 160:1796–1803[PubMed]
    [Google Scholar]
  12. Sciorati C, Rovere P, Ferrarini M, Paolucci C, Heltai S et al. Generation of nitric oxide by the inducible nitric oxide synthase protects gamma delta T cells from Mycobacterium tuberculosis-induced apoptosis. J Immunol 1999; 163:1570–1576[PubMed]
    [Google Scholar]
  13. Kuo HP, Wang CH, Huang KS, Lin HC, Yu CT et al. Nitric oxide modulates interleukin-1beta and tumor necrosis factor-alpha synthesis by alveolar macrophages in pulmonary tuberculosis. Am J Respir Crit Care Med 2000; 161:192–199 [CrossRef][PubMed]
    [Google Scholar]
  14. Grasemann H, Michler E, Wallot M, Ratjen F. Decreased concentration of exhaled nitric oxide (NO) in patients with cystic fibrosis. Pediatr Pulmonol 1997; 24:173–177 [CrossRef][PubMed]
    [Google Scholar]
  15. Keen C, Gustafsson P, Lindblad A, Wennergren G, Olin A-C. Low levels of exhaled nitric oxide are associated with impaired lung function in cystic fibrosis. Pediatr Pulmonol 2010; 45:n/a–248 [CrossRef][PubMed]
    [Google Scholar]
  16. Ratjen F, Gärtig S, Wiesemann HG, Grasemann H. Effect of inhaled nitric oxide on pulmonary function in cystic fibrosis. Respir Med 1999; 93:579–583 [CrossRef][PubMed]
    [Google Scholar]
  17. Grasemann H, Tullis E, Ratjen F. A randomized controlled trial of inhaled L-arginine in patients with cystic fibrosis. J Cyst Fibros 2013; 12:468–474 [CrossRef][PubMed]
    [Google Scholar]
  18. Ghaffari A, Miller CC, McMullin B, Ghahary A. Potential application of gaseous nitric oxide as a topical antimicrobial agent. Nitric Oxide 2006; 14:21–29 [CrossRef][PubMed]
    [Google Scholar]
  19. Miller C, McMullin B, Ghaffari A, Stenzler A, Pick N et al. Gaseous nitric oxide bactericidal activity retained during intermittent high-dose short duration exposure. Nitric Oxide 2009; 20:16–23 [CrossRef][PubMed]
    [Google Scholar]
  20. Miller CC, Hergott CA, Rohan M, Arsenault-Mehta K, Döring G et al. Inhaled nitric oxide decreases the bacterial load in a rat model of Pseudomonas aeruginosa pneumonia. J Cyst Fibros 2013; 12:817–820 [CrossRef][PubMed]
    [Google Scholar]
  21. Miller C, Miller M, McMullin B, Regev G, Serghides L et al. A phase I clinical study of inhaled nitric oxide in healthy adults. J Cyst Fibros 2012; 11:324–331 [CrossRef][PubMed]
    [Google Scholar]
  22. Deppisch C, Herrmann G, Graepler-Mainka U, Wirtz H, Heyder S et al. Gaseous nitric oxide to treat antibiotic resistant bacterial and fungal lung infections in patients with cystic fibrosis: a phase I clinical study. Infection 2016; 44:513–520 [CrossRef][PubMed]
    [Google Scholar]
  23. Yaacoby-Bianu K, Gur M, Toukan Y, Nir V, Hakim F et al. Compassionate nitric oxide adjuvant treatment of persistent Mycobacterium infection in cystic fibrosis patients. Pediatr Infect Dis J 2017
    [Google Scholar]
  24. Bentur L, Gur M, Ashkenazi M, Livnat-Levanon G, Mizrahi M et al. Pilot study to test inhaled nitric oxide in cystic fibrosis patients with refractory Mycobacterium abscessus lung infection. J Cyst Fibros 2020; 19:225-231 [CrossRef][PubMed]
    [Google Scholar]
  25. Ghaffari A, Neil DH, Ardakani A, Road J, Ghahary A et al. A direct nitric oxide gas delivery system for bacterial and mammalian cell cultures. Nitric Oxide 2005; 12:129–140 [CrossRef][PubMed]
    [Google Scholar]
  26. Quittner AL, Modi AC, Wainwright C, Otto K, Kirihara J et al. Determination of the minimal clinically important difference scores for the cystic fibrosis Questionnaire-Revised respiratory symptom scale in two populations of patients with cystic fibrosis and chronic Pseudomonas aeruginosa airway infection. Chest 2009; 135:1610–1618 [CrossRef][PubMed]
    [Google Scholar]
  27. Aitken ML, Limaye A, Pottinger P, Whimbey E, Goss CH et al. Respiratory outbreak of Mycobacterium abscessus subspecies massiliense in a lung transplant and cystic fibrosis center. Am J Respir Crit Care Med 2012; 185:231–232 [CrossRef][PubMed]
    [Google Scholar]
  28. da Silva JL, Nguyen J, Fennelly KP, Zelazny AM, Olivier KN. Survival of pathogenic Mycobacterium abscessus subsp. massiliense in Acanthamoeba castellanii. Res Microbiol 2018; 169:56–60 [CrossRef][PubMed]
    [Google Scholar]
  29. Tettelin H, Davidson RM, Agrawal S, Aitken ML, Shallom S et al. High-Level relatedness among Mycobacterium abscessus subsp. massiliense strains from widely separated outbreaks. Emerg Infect Dis 2014; 20:364–371 [CrossRef][PubMed]
    [Google Scholar]
  30. Sriramulu DD, Lünsdorf H, Lam JS, Römling U. Microcolony formation: a novel biofilm model of Pseudomonas aeruginosa for the cystic fibrosis lung. J Med Microbiol 2005; 54:667–676 [CrossRef][PubMed]
    [Google Scholar]
  31. Ferro BE, van Ingen J, Wattenberg M, van Soolingen D, Mouton JW. Time-kill kinetics of antibiotics active against rapidly growing mycobacteria. J Antimicrob Chemother 2015; 70:811–817 [CrossRef][PubMed]
    [Google Scholar]
  32. Griffith DE, Adjemian J, Brown-Elliott BA, Philley JV, Prevots DR et al. Semiquantitative culture analysis during therapy for Mycobacterium avium complex lung disease. Am J Respir Crit Care Med 2015; 192:754–760 [CrossRef][PubMed]
    [Google Scholar]
  33. Wright RO, Lewander WJ, Woolf AD. Methemoglobinemia: etiology, pharmacology, and clinical management. Ann Emerg Med 1999; 34:646–656 [CrossRef][PubMed]
    [Google Scholar]
  34. Cortazzo JA, Lichtman AD. Methemoglobinemia: a review and recommendations for management. J Cardiothorac Vasc Anesth 2014; 28:1043–1047 [CrossRef][PubMed]
    [Google Scholar]
  35. Linn WS, Shamoo DA, Spier CE, Valencia LM, Anzar UT et al. Controlled exposure of volunteers with chronic obstructive pulmonary disease to nitrogen dioxide. Arch Environ Health 1985; 40:313–317 [CrossRef][PubMed]
    [Google Scholar]
  36. Linn WS, Solomon JC, Trim SC, Spier CE, Shamoo DA et al. Effects of exposure to 4 ppm nitrogen dioxide in healthy and asthmatic volunteers. Arch Environ Health 1985; 40:234–239 [CrossRef][PubMed]
    [Google Scholar]
  37. CDC 2020; The National Institute for Occupational Safety and Health (NIOSH). https://www.cdc.gov/niosh/idlh/10102440.html April 16, 2020
  38. Park IK, Hsu AP, Tettelin H, Shallom SJ, Drake SK et al. Clonal diversification and changes in lipid traits and colony morphology in Mycobacterium abscessus clinical isolates. J Clin Microbiol 2015; 53:3438–3447 [CrossRef][PubMed]
    [Google Scholar]
  39. Singh R, Manjunatha U, Boshoff HIM, Ha YH, Niyomrattanakit P et al. PA-824 kills nonreplicating Mycobacterium tuberculosis by intracellular NO release. Science 2008; 322:1392–1395 [CrossRef][PubMed]
    [Google Scholar]
  40. Thompson AM, Bonnet M, Lee HH, Franzblau SG, Wan B et al. Antitubercular nitroimidazoles revisited: synthesis and activity of the authentic 3-nitro isomer of Pretomanid. ACS Med Chem Lett 2017; 8:1275–1280 [CrossRef][PubMed]
    [Google Scholar]
  41. Fernandes GFDS, de Souza PC, Marino LB, Chegaev K, Guglielmo S et al. Synthesis and biological activity of furoxan derivatives against Mycobacterium tuberculosis . Eur J Med Chem 2016; 123:523–531 [CrossRef][PubMed]
    [Google Scholar]
  42. Garbe TR, Hibler NS, Deretic V. Response to reactive nitrogen intermediates in Mycobacterium tuberculosis: induction of the 16-kilodalton alpha-crystallin homolog by exposure to nitric oxide donors. Infect Immun 1999; 67:460–465 [CrossRef][PubMed]
    [Google Scholar]
  43. Voskuil MI, Schnappinger D, Visconti KC, Harrell MI, Dolganov GM et al. Inhibition of respiration by nitric oxide induces a Mycobacterium tuberculosis dormancy program. J Exp Med 2003; 198:705–713 [CrossRef][PubMed]
    [Google Scholar]
  44. Weinberger B, Laskin DL, Heck DE, Laskin JD. The toxicology of inhaled nitric oxide. Toxicol Sci 2001; 59:5–16 [CrossRef][PubMed]
    [Google Scholar]
  45. Neonatal Inhaled Nitric Oxide Study Group Inhaled nitric oxide and hypoxic respiratory failure in infants with congenital diaphragmatic hernia. Pediatrics 1997; 99:838–845 [CrossRef]
    [Google Scholar]
  46. Regev-Shoshani G, Vimalanathan S, McMullin B, Road J, Av-Gay Y et al. Gaseous nitric oxide reduces influenza infectivity in vitro. Nitric Oxide 2013; 31:48–53 [CrossRef][PubMed]
    [Google Scholar]
  47. Miller CC, Rawat M, Johnson T, Av-Gay Y. Innate protection of Mycobacterium smegmatis against the antimicrobial activity of nitric oxide is provided by mycothiol. Antimicrob Agents Chemother 2007; 51:3364–3366 [CrossRef][PubMed]
    [Google Scholar]
  48. Long R, Jones R, Talbot J, Mayers I, Barrie J et al. Inhaled nitric oxide treatment of patients with pulmonary tuberculosis evidenced by positive sputum smears. Antimicrob Agents Chemother 2005; 49:1209–1212 [CrossRef][PubMed]
    [Google Scholar]
  49. Howlin RP, Cathie K, Hall-Stoodley L, Cornelius V, Duignan C et al. Low-Dose nitric oxide as targeted anti-biofilm adjunctive therapy to treat chronic Pseudomonas aeruginosa infection in cystic fibrosis. Mol Ther 2017; 25:2104–2116 [CrossRef][PubMed]
    [Google Scholar]
  50. Privett BJ, Deupree SM, Backlund CJ, Rao KS, Johnson CB et al. Synergy of nitric oxide and silver sulfadiazine against gram-negative, Gram-positive, and antibiotic-resistant pathogens. Mol Pharm 2010; 7:2289–2296 [CrossRef][PubMed]
    [Google Scholar]
http://instance.metastore.ingenta.com/content/journal/acmi/10.1099/acmi.0.000154
Loading
/content/journal/acmi/10.1099/acmi.0.000154
Loading

Data & Media loading...

Supplements

Supplementary material 1

PDF

Most cited this month Most Cited RSS feed

This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error