Sunday, June 21, 2015

AAC: LPAI H7N9 Acquires Antiviral Resistance When Exposed To Environmental Oseltamivir


Photo Credit USGS – Wastewater: The Primary Treatment Process

1. Screening 2. Pumping 3. Aerating 4. Removing sludge 5. Removing Scum 6. killing bacteria




Almost 10,000 blog entries ago, in The Law of Unintended Consequences (Jan ‘07), I wrote about growing concerns over what effects the large-scale use of Oseltamivir (Tamiflu ®) might have on the environment and the evolution of avian flu viruses (see study Potential Risks Associated with the Proposed Widespread Use of Tamiflu).  


Tamiflu, you see, is excreted almost 100% intact in one’s urine, and can eventually make its way through wastewater treatment plants and end up in the environment where it could potentially impact the evolution of avian viruses carried by waterfowl.


These concerns re-emerged in the fall of 2009 (see Everything Old Is News Again) when researchers at Kyoto University tested wastewater discharge from three local sewage treatment plants and water from two rivers into which they drained during the 2008-09 flu season looking for signs of the active ingredient in Tamiflu, oseltamivir carboxylate (OC).

For years Japan has been the largest consumer of antivirals for seasonal flu, and they found exactly what they were looking for; substantial levels of the Tamiflu metabolite in the environment.

A couple of years later, in Pandemics & The Law Of Unintended Consequences, we looked at not only the potential effects of antivirals in our sewage system, but also how the consumption (and excretion) of antibiotics during a pandemic might affect wastewater treatment plants (WWTPs).


Specifically that antibiotics in the sewage could inhibit microbial activity, resulting in the failure of WWTPs and the discharge of under-treated wastewater into the environment (see Centre for Ecology & Hydrology 2-Mar-2011 Effectiveness of wastewater treatment may be damaged during a severe flu pandemic).


Carrying the WWTP story one step further, in WWTPs As `Mixing Vessels’ For Resistant Bacteria, UK scientists discovered that sewage plants were actually amplifying the number of resistant bacteria that entered the plant.  


But I digress . . .  Back to the Tamiflu angle.


The concern has been that very low levels of oseltamivir could make its way into rivers and ponds as treated water is released into the environment.  Birds - the natural hosts of avian flu strains - would be exposed and this might induce the avian flu viruses they carry to develop antiviral resistance.

As the following study shows, researchers from Sweden replicated these conditions using a (European) LPAI H7N9 virus in Mallard ducks.. The surprise here isn’t that avian flu viruses exposed to low levels of oseltamivir picked up amino acid changes that enabled antiviral resistance.


The surprise is it only took 2 days.


This from ASM’s  Antimicrobial Agents and Chemotherapy.


Influenza A(H7N9) Acquires Resistance Related NA-I222T Substitution when Infected Mallards are Exposed to Low Levels of Oseltamivir in Water.

Anna Gillman1,2#, Marie Nykvist1,2,  Shaman Muradrasoli2,3,  Hanna Söderström4,  Michelle Wille5,  Annika  Daggfeldt6,  Caroline Bröjer7, Jonas Waldenström5,  Björn Olsen1,2 and  Josef D. Järhult1,2



Influenza A virus (IAV) has its natural reservoir in wild waterfowl and new human IAVs often contain gene segments originating from avian IAVs. Treatment options for severe human influenza are principally restricted to neuraminidase inhibitors (NAIs), among which oseltamivir is stockpiled in preparedness for influenza pandemics. There is evolutionary pressure in the environment for resistance development to oseltamivir in avian IAVs, as the active metabolite oseltamivir carboxylate (OC) passes largely un-degraded through sewage treatment to river water where waterfowl reside.

In an in vivo Mallard (Anas platyrhynchos) model, we tested if low-pathogenic avian influenza A(H7N9) virus could become resistant if the host was exposed to low levels of OC. Ducks were experimentally infected and OC was added to their water, where after infection and transmission was maintained by successive introductions of uninfected birds. Daily fecal samples were tested for IAV excretion, genotype and phenotype.

Following Mallard exposure of 2.5 μg/L OC, the resistance related NA-I222T substitution, was detected within 2 days during the first passage and was found in all viruses sequenced from subsequently introduced ducks.

The substitution generated 8-fold and 2.4-fold increase in IC50 for OC (p< 0.001) and zanamivir (p = 0.016), respectively. We conclude that OC exposure of IAV hosts, in the same concentration magnitude as found in the environment, may result in amino acid substitutions leading to changed antiviral sensitivity in an IAV subtype that can be highly pathogenic to humans. A prudent use of oseltamivir and resistance surveillance of IAVs in wild birds is warranted.


The entire study is available as a preliminary PDF File.  The authors sum up their findings by writing:


To better understand the emergence and persistence of resistant IAVs, it is important to further study possible transmission of avian IAVs containing resistance related mutations from wild birds to poultry, humans and other mammals.

As resistance mutation(s)  in an A(H7N9) virus, or in another novel human-pathogenic IAV with pandemic potential, poses a public health threat, our results stress the need for prudent antiviral use and better  sewage treatment as preventive measures, as well as resistance surveillance of IAVs in wild birds.

1 comment:

Michael Coston said...

A brief response to a reader who left a comment (removed) saying that `Tamiflu doesn't work', and speculated on why scientists would claim otherwise.

While I understand the BMJ and the Cochrane group have launched a campaign against Roche, and their drug Tamiflu, there is ample evidence that Tamiflu IS EFFECTIVE when used early, and for severe influenza.

The CDC, PHE, and WHO all agree (links below).

I'm sure your opinions are heartfelt - but I don't want this blog to become a place to speculate on the motives of other people.