Gaseous nitric oxide bactericidal activity retained during intermittenthigh-dose short duration exposure

摘要

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 anti-microbial attributes may be useful for pulmonary infections. However, gNO would have limited useful-ness as an inhaled antimicrobial agent as continuous exposure to the concentration required for abactericidal effect (160-200 ppm) leads to methemoglobinemia. To overcome this problem, we investi-gated whether a thirty minute exposure of 160 ppm every four hours would retain the same antimicro-bial effect as continuous delivery. In vitro, exposure of clinical multi-drug resistant Staphylococcus aureus and Escherichia coli strains iso-lated from the lungs of nosocomial pneumonia patients and a lethal antibiotic-resistant strain of Pseudo-monas aeruginosa, isolated from a deceased cystic fibrosis patient resulted in over a 5 logi 0 reduction inbacterial load after multiple thirty minute treatments (4 cycles) every four hours to 160 ppm gNO. Theintermittent regimen required 320 (SD 0) ppm h for 100% lethality whereas the continuous exposurerequired 800 (SD 160) ppm h. We have also shown that selection for a gNO resistant phenotype didnot lead to decrease sensitivity to gNO therapy (p > 0.05). In addition, no host cellular toxicity wasobserved in human THP-1 monocytes and macrophages following intermittent delivery of a high concen-tration of gNO, and the proliferation and migration of pulmonary epithelial cells was not adverselyaffected by the administration of intermittent high-dose gNO. These results justify further studies thatshould focus on whether intermittent delivery of 160 ppm of gNO every four hours can technically beadministered while keeping inhaled NO2 levels less than2 ppm and methemoglobin saturation less than2.5 percent.