Abstract
Background:There is a continued need for strategies to prevent influenza. While cetylpyridinium chloride (CPC), a broad-spectrum antimicrobial agent, has an extensive antimicrobial spectrum, its ability to affect respiratory viruses has not been studied in detail.Objectives:Here, we evaluate the ability of CPC to disrupt influenza viruses in vitro and in vivo.Methods:The virucidal activity of CPC was evaluated against susceptible and oseltamivir- resistant strains of influenza viruses. The effective virucidal concentration (EC) of CPC was determined using a hemagglutination assay and tissue culture infective dose assay. The effect of CPC on viral envelope morphology and ultrastructure was evaluated using transmission electron microscopy (TEM). The ability of influenza virus to develop resistance was evaluated after multiple passaging in sub-inhibitory concentrations of CPC. Finally, the efficacy of CPC in formulation to prevent and treat influenza infection was evaluated using the PR8 murine influenza model.Results:The virucidal effect of CPC occurred within 10 minutes, with mean EC50 and EC2log ranging between 5 to 20 μg/mL, for most strains of influenza tested regardless of type and resistance to oseltamivir. Examinations using TEM showed that CPC disrupted the integrity of the viral envelope and its morphology. Influenza viruses demonstrated no resistance to CPC despite prolonged exposure. Treated mice exhibited significantly increased survival and maintained body weight compared to untreated mice.Conclusions:The antimicrobial agent CPC possesses virucidal activity against susceptible and resistant strains of influenza virus by targeting and disrupting the viral envelope. Substantial virucidal activity is seen even at very low concentrations of CPC without development of resistance. Moreover, CPC in formulation reduces influenza-associated mortality and morbidity in vivo.
Highlights
Influenza is responsible for substantial morbidity and mortality worldwide [1,2,3,4,5]
We found that the percentage effective concentration of cetylpyridinium chloride (CPC) (EC50) against all influenza viruses ranged between 5 μg/mL and 12.5 μg/mL (Table 1) by hemagglutination assay
Influenza A required higher concentrations of CPC to reduce the titer by 50% (H1N1:12.5 ± 5.6 μg/mL, H3N2: 10 ± 5.0 μg/mL), whereas influenza B was significantly more susceptible to the disrupting effects of CPC (5 ± 1.9 μg/mL, P = 0.001)
Summary
Influenza is responsible for substantial morbidity and mortality worldwide [1,2,3,4,5]. Influenza is estimated to adversely affect up to 5% to 10% of adults and 20% to 30% of children each year [6]. Current prevention strategies for influenza are dependent on the use of anti-influenza medications and vaccines. NAIs confer only modest decreases in symptom duration for individuals presenting with uncomplicated illness [11,12,13], and this treatment suffers from the selection of resistant strains, adverse effects, and high cost [14,15,16]. While the most effective way to prevent influenza disease and its severe outcomes is by vaccination, current coverage estimates are well below the Healthy People 2020 goal of 70% [17, 18]. The development of effective novel strategies to prevent and treat influenza disease is a significant unmet need. While cetylpyridinium chloride (CPC), a broad-spectrum antimicrobial agent, has an extensive antimicrobial spectrum, its ability to affect respiratory viruses has not been studied in detail
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