Naegleria fowleri is a summertime villain scary and sensational, the “Brain-eating Amoeba.” Even the name is villainous. It is an amoeba that lives in fresh water, especially warm water, and is a cause of brain infections, almost always resulting in death.
The attention that has been focused on Naegleria in recent weeks has led me to wonder about our focus on this and on our priorities, and what we can learn from this about drug development. Did you know that this parasite has only killed 128 people in the US in the last 50 years? Your chance of being struck by lightening is far greater—about 30 people in the US die per year from that.
The good news, besides the rarity of the infection, is theannouncement of a new treatment, miltefosine. Let’s look first at amoeba infections, at the new treatment, and then at the broader implications for drug repurposing.
Naegleria fowleri is found throughout the world, and infections have been associated with fresh water exposure, often summertime swimming in lakes or even backyard wading pools. It can occur anytime water goes up the nose, especially forcefully, as when children play. Perhaps the most bizarre case report I encountered was that of “8-month-old infant thought to have acquired an infection with N. fowleri during a full-submersion baptism ceremony in a natural body of water.”
Infection occurs most commonly in children. In the US, it is more common in the South, consistent with the organism’s affinity for warmer water. In recent years, however, cases have been reported from the middle of the US and as far north as Minnesota.
Related amoeba species, Balamuthia mandrillaris and Acanthamoebacan cause granulomatous amoebic encephalitis. Acanthamoeba have also been associated with contact lens infections.
Nasal irrigation with water is another risk for infections. It is a ritual in some religions. Nasal irrigation is also sometimes used as part of the treatment of chronic sinus infections. Such treatment with neti pots was associated with an outbreak of “primary amoebic meningoencephalitis.” Use of boiled or sterile solutions can prevent infection, though chlorine is also an adequate disinfectant in appropriate concentrations. It is important to note that Naegleria infections are not acquired by drinking contaminated water, but only by water that goes up the nose, then traveling via the olfactory (smell) nerve to the brain.
Acanthamoeba haven’t been in the news as much of late. Unlike Naegleria, this amoeba only causes encephalitis in immunocompromised patients. It has most been known for causing severe eye infections (keratitis) in contact lens wearers. There was a widespread outbreak of this in 2007, associated with contact lens solution, not through intrinsically contaminated product, but likely through contamination during use.
Another rare amoebic pathogen is Balamuthia mandrillaris, which also causes a deadly encephalitis, and can affect normal people. It can be acquired through the nose. Both Acanthamoeba and Balamuthia are also sometimes acquired through breaks in skin.
There are no practical ways of avoiding Naegleria while enjoying summer water activities, other than by keeping your head above water or using nose clips. Hotter water from thermal pools or industrial effluent (like Mt. Storm, WV, used for diving lessons, popular because of the warmth) poses an increased risk. While not yet demonstrated, one might expect increased infections as global warming worsens.
In terms of nasal irrigations, use water that has been previously boiled or distilled or sterile water.
To avoid Acanthamoeba keratitis, only sterile contact solution should be used, and never diluted with tap water.
There have been rare survivors of amoebic encephalitis, who were treated with an antifungal, Amphotericin B—the drug is so toxic and unpleasant, it has been nicknamed “Amphoterrible”—in addition to other antifungals. CDC has also recommended the addition of Azithromycin based on in vitro and mouse models.
This week the CDC announced the availability of miltefosine for treatment of these amoeba infections. Originally developed for oncology (cancer treatment), miltefosine is not an entirely new drug; it has been used as investigational treatment of a tropical parasitic infection, Leishmania, in the US. Primary side effects are gastrointestinal, although it causes some mild nephrotoxicity (kidney damage). Miltefosine was also used successfully in combinationwith fluconazole and albendazole, following failed Amphotericin, in one case of Balmuthia.
Miltefosine is an exciting addition because it is given orally, which is extraordinarily important, especially in developing countries.
Implications - Drug Repurposing
Miltefosine’s use for Naegleria is exciting, in part, because it is using a drug for a different parasitic infection, Leishmania. This parasite is transmitted by sandflies and largely occurs outside the US or in returning military personnel. Miltefosine has long been used to treat Leishmania; it has now been found to be effective for this amoeba. So while it is “investigational” in the US and for this indication, there is already considerable experience with the drug worldwide. In 2011, miltefosine was added to the World Health Organization’s List of Essential Medicines. Curiously, the drug was originally developed to treat cancer. A topical solution of Miltefosine is approved for treatment of skin metastases from breast cancer. Animal studies suggest that miltefosine may also be useful for other parasitic and fungal infections.
Drug repurposing may similarly provide a much more rapid drug development route than traditional drug discovery, since it would require much less investment of time and money. It would be applicable for more common infections, such as superbugs. For example, an off-patent antifungal drug, ciclopirox, is being tested against drug resistant Acinetobacater baumanii, one of the “superbugs” of increasing concern.
Last year, National Institutes of Health (NIH) National Center for Advancing Translational Sciences (NCATS) announced a new initiative for drug repurposing. A number of pharmaceutical companies, including Pfizer, AstraZeneca, Eli Lilly, Abbott, Bristol-Myers Squibb, GlaxoSmithKline, Janssen Pharmaceuticals, and Sanofi, agreed to provide more than 50 compounds for a pilot program of repurposing existing or failed candidate drugs. A similar initiative has been developed in the UK as well. There, AstraZeneca has not only provided compounds but, perhaps equally importantly, has put considerable information about these drugs into public domain. An excellent review is here.
Recently, considerable attention has been paid by the popular press to the two Naeglaria infections in children this year. In contrast, little attention is devoted to huge impact of carbapenem-resistant Enterobacteriaceae infections, that I reported on here. Yet, per the CDC "in 2012, 4.6% of acute-care hospitals reported at least one CRE HAI (healthcare associated infection) (short-stay hospitals, 3.9%; long-term acute-care hospitals, 17.8%). The proportion of Enterobacteriaceae that were CRE increased from 1.2% in 2001 to 4.2% in 2011." Clearly, a number of hospitals and long-term care facilities—even the NIH—have experienced outbreaks in recent years.
The Naegleria story is important because it illustrates the need for better understandings of pathogenesis of diseases and why only a few unlucky people become infected when many are exposed to amoeba. It also demonstrates the need and value of drug repurposing.
It is a shameful waste to not recognize the potential of an available drug for reuse, especially when there are few other options. It is a greater waste to use our limited armamentarium of drugs for resistant organisms unnecessarily, squandering them by inappropriate use leading to resistance. Thriftiness is a lost value that is sorely needed now. Certain antibiotics should be restricted for the good of the broad community of people. And instead of focusing on a few sensational and tragic cases, media should focus more attention on the bigger immediate threat of antibiotic resistant organisms.
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images from CDC