Gaseous nitric oxide bactericidal activity retained during intermittent high-dose short duration exposure.
Previously, we have shown that gaseous Nitric oxide (gNO) has great potential as an effective topical anti-infective agent for non-healing wounds due to its non-specific antimicrobial properties. These same antimicrobial attributes may be useful for pulmonary infections. However, gNO would have limited usefulness as an inhaled antimicrobial agent as continuous exposure to the concentration required for a bactericidal effect (160-200 ppm) leads to methemoglobinemia. To overcome this problem, we investigated whether a thirty minute exposure of 160 ppm every four hours would retain the same antimicrobial effect as continuous delivery. In vitro, exposure of clinical multi-drug resistant Staphylococcus aureus and Escherichia coli strains isolated from the lungs of nosocomial pneumonia patients and a lethal antibiotic-resistant strain of Pseudomonas aeruginosa, isolated from a deceased cystic fibrosis patient resulted in over a 5 log(10) reduction in bacterial load after multiple thirty minute treatments (4 cycles) every four hours to 160 ppm gNO. The intermittent regimen required 320 (SD=0)ppm h for 100% lethality whereas the continuous exposure required 800 (SD=160)ppm h. We have also shown that selection for a gNO resistant phenotype did not lead to decrease sensitivity to gNO therapy (p>0.05). In addition, no host cellular toxicity was observed in human THP-1 monocytes and macrophages following intermittent delivery of a high concentration of gNO, and the proliferation and migration of pulmonary epithelial cells was not adversely affected by the administration of intermittent high-dose gNO. These results justify further studies that should focus on whether intermittent delivery of 160 ppm of gNO every four hours can technically be administered while keeping inhaled NO(2) levels less than 2 ppm and methemoglobin saturation less than 2.5 percent.
Miller
Chris
C
Division of Infectious Diseases, Department of Medicine, Vancouver Coastal Health at Vancouver General Hospital, University of British Columbia, 2733 Heather Street, Vancouver, BC, Canada. miller42@interchange.ubc.ca
McMullin
Bevin
B
Ghaffari
Abdi
A
Stenzler
Alex
A
Pick
Neora
N
Roscoe
Diane
D
Ghahary
Aziz
A
Road
Jeremy
J
Av-Gay
Yossef
Y
D000280:Administration, Inhalation; D000890:Anti-Infective Agents / Q000008:administration & dosage* / Q000494:pharmacology*; D045744:Cell Line, Tumor; D004926:Escherichia coli / Q000187:drug effects; D006801:Humans; D008264:Macrophages / Q000187:drug effects; D008706:Methemoglobin / Q000009:adverse effects; D009000:Monocytes / Q000187:drug effects; D009569:Nitric Oxide / Q000008:administration & dosage* / Q000494:pharmacology*; D011550:Pseudomonas aeruginosa / Q000187:drug effects; D013211:Staphylococcus aureus / Q000187:drug effects
D000890:Anti-Infective Agents; D009569:Nitric Oxide; D008706:Methemoglobin