Photo Credit
USGS – Wastewater:
The Primary Treatment Process
1. Screening 2. Pumping 3. Aerating 4. Removing sludge 5.
Removing Scum 6. killing bacteria
#19,350
Almost 20 years ago (January 2007), in
The Law of Unintended Consequences, we looked at a study by researchers at the
Centre for Ecology and Hydrology in Oxford titled
Potential Risks Associated with the Proposed Widespread Use of Tamiflu, that questioned what might happen if millions of people simultaneously began taking Tamiflu and releasing it into our environment.
A large percentage (60%-80%) of the Tamiflu (aka oseltamivir) a person takes is eventually excreted in their urine as oseltamivir carboxylate (OC), a factoid that 20 years ago briefly led to internet speculation about the practice of ‘recycling’ our own urine, to stretch out the supply of Tamiflu during a crisis.
While
that thankfully never became an internet challenge, it did inspire a doctor to
publish a proposal in
Nature on the co-administration of a generic gout medicine -
probenecid - which slows the excretion of certain drugs - potentially increasing the effectiveness
(and lowering the overall dose) of oseltamivir.
The 2006 Oxford study specifically warned that large quantities of
oseltamivir carboxylate (OC) could be excreted into sewers during a pandemic - which wastewater plants are largely unable to remove - and could end up in rivers and streams, and eventually birds, where it might promote antiviral resistance in avian flu viruses.
Similar 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.
In 2011, 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).
But a proof of concept was published in 2015, in
AAC: LPAI H7N9 Acquires Antiviral Resistance When Exposed To Environmental Oseltamivir, which reported that mallards experimentally infected with
LPAI H7N9, and then exposed to low levels of oseltamivir carboxylate (OC) in their water,
developed antiviral resistance markers (NA-I222T) in as few as 2 days.
From the Abstract:
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.
Two of those same authors (
Lindström & Järhult) are back with today's report, which provides a relative risk assessment of introducing four different antivirals (
3 Neuraminidase inhibitors (NAIs)
, plus Amantadine, an M2 ion-channel inhibitor) into aquatic environments.
The authors report that the use of
PE (
peramivir) and
OC (
oseltamivir) pose the highest environment risk, and suggest using ZA (
zanamivir) whenever possible, and limiting the use of oseltamivir in uncomplicated influenza in non-risk groups.
Zanamivir, however, isn't always a good substitute for oseltamivir because it is an inhaled powder, which can be problematic for those with COPD, asthma, or who are experiencing respiratory symptoms.
They also recommend stockpiling Baloxavir (see yesterday's blog
EID Journal: Comparison of Baloxavir-Based Combinations and Monotherapies for Treating Influenza A(H5N1) Clade 2.3.4.4b Virus Infection in Mice) to provide additional therapeutic options.
This is a lengthy, and times technical report. Follow the link to read it in its entirety. I'll have a postscript after the break.
Abstract
Influenza antivirals (IAs) have been detected in aquatic environments inhabited by dabbling ducks, the natural reservoir of influenza A virus (IAV), raising concerns about the development of antiviral resistance. Because novel human IAV strains often contain genetic material of avian origin, this may contribute to resistance in viruses with pandemic potential.
This study aimed to assess the environmental risk posed by four IAs—oseltamivir carboxylate (OC), zanamivir (ZA), peramivir (PE), and amantadine (AM)—based on their potential for environmental release, environmental stability, and induction of antiviral resistance. The assessment combined data from new experiments on (1) environmental release and (2) environmental stability of PE, AM, OC, and ZA, with results from previously published in vivo experiments in a mallard model examining (3) resistance development to OC, PE, and ZA in IAV.
The risk of environmental release was assessed as high for OC, AM, and PE, and very high for ZA. Environmental stability ranged from very high to low, in the order PE > AM > OC > ZA. The potential to induce resistance in IAV was similar for PE and OC, and lower for ZA.
Overall, the environmental risk ranking was PE > OC > ZA, with PE and OC posing the highest risks.
Prudent use of IAs requires balancing the risk of resistance development against clinical benefit. In cases of complicated influenza or in high-risk patient groups, the clinical benefits are substantial and justify IA use. However, in uncomplicated influenza among otherwise healthy individuals, the clinical benefit is limited, and the risk of resistance development should be carefully considered. Among the evaluated antivirals, ZA showed the lowest environmental risk and should be preferred when feasible.
(SNIP)
Conclusions
This is the first study to jointly assess the environmental risk of influenza antivirals (IAs), and the public health risk caused by environmental resistance development in influenza A viruses (IAVs). This comprehensive approach provides new knowledge to support sustainable antiviral use, helping to prevent resistance development in future pandemics and preserve the effectiveness of antiviral stockpiles.
Our study shows that the environmental occurrence of IAs, and resistance development in IAVs in aquatic environments, is a concern for all three IAs (OC, PE, and ZA) studied with a high environmental risk of both PE and OC. Our risk assessment was based on virus experiments on individual IAs which could underestimate the risk for environmental resistance development due to cocktail effects in natural environments.
As antiviral drugs constitute a cornerstone in pandemic preparedness, especially in the first phase before vaccines can be mass-produced, it is crucial to work to retain their effectiveness. Given our assessment of the high environmental risk of both PE and OC, and the risk for the resistance developed to be part of a novel IAV with pandemic potential in humans, non-pandemic use should be prudent. This includes balancing benefits of pre-pandemic use with risks of a resistant pandemic IAV. IAs are important in treating complicated diseases and diseases in risk groups and should be used in these cases. However, in uncomplicated influenza in non-risk groups we argue that the clinical benefit is minimal, and if the use is extensive, it will drive environmental occurrence and risk for resistance development. Therefore, we argue that the risk for resistance development should be considered when treating uncomplicated influenza in non-risk groups.
From our risk assessment, it seems beneficial to use ZA rather than oseltamivir phosphate (the pro-drug for OC) when practically possible. PE is the IA with the highest environmental risk in our assessment, hence highest public health risk and other alternatives should be used when possible. As PE is at present only available as an intravenous formulation, it is likely that the use of this drug will not be extensive.
New influenza antivirals such as baloxavir are a very important addition to the treatment arsenal. They should be considered as additions to stockpiles in pandemic preparedness to have access to alternate antivirals with a different mode of action. This will increase the chances of a viable treatment option in case of a resistant pandemic IAV. At the same time, it is crucial to evaluate the risk for environmental resistance development potential of new antivirals to guide prudent pre-pandemic use.
(Continue . . . )
Antivirals, antibiotics, and most antifungal medicals all share the same
Achilles' heel. Over time - and particularly if they are used recklessly or excessively - the pathogens
(viruses, bacteria, or fungi) they were designed to suppress can evolve or mutate enough to render them ineffective.
While many people fear that a hyper-virulent novel virus will someday emerge and kill hundreds of millions of people, the reality is - if we don't protect our limited armamentarium of antibiotics and antivirals - something relatively ordinary, and previously treatable, could do the job equally as well.
But balancing today's needs with those of tomorrow is always easier said than done. For more on the potential environmental risks from wastewater treatment plants, you may wish to revisit:
https://afludiary.blogspot.com/2026/09/plos-one-occurrence-of-influenza.html
