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The FDA approved baloxavir marboxil (brand name Xofluza) on October 24. It was on the fast track* for approval by the FDA, and they had agreed to deliver their ruling by December 24; they beat that deadline by a good bit. Baloxavir is a completely new type of anti-influenza drug, acting on an earlier stage of influenza virus replication in the host cell than does the more familiar oseltamivir (brand name Tamiflu).

(slide 34 at http://www.shionogi.co.jp/en/ir/pdf/e_p151030.pdf; S-033188 was the name for baloxavir during early stages of research)

Not at all by coincidence, I held a journal club for infectious diseases fellows and faculty at my house last week to discuss the New England Journal article from September 6 (Hayden FG, et al, 379:913) that reported on 2 trials of baloxavir. I imagined the drug being approved by the FDA on Christmas Eve, right before the deadline, followed shortly thereafter by a call from 1 of you readers to our on-call fellow or attending physician asking for advice on use of this new agent. We went through the article, including the supplementary online tables and graphs and the 400-page document detailing all of the study protocol details, with a fine-tooth comb. It really was a well-designed set of studies, but the results may be somewhat more limited than you might hope. Here are a few of the key points we discussed:

1. The studies combined included just under 2000 patients, but most were adults. Bottom line: baloxavir had a modest effect on duration of symptoms compared to placebo, but no real clinical benefit when compared to influenza patients receiving oseltamivir.
2. All of the patients had to be enrolled within 48 hours of illness onset.
3. Only about 200 children (the exact number was hard to determine from the report), none younger than 12 years of age, actually received baloxivir. None of the 12-19 year olds received oseltamivir, the only comparison was to approximately 100 placebo subjects. (Part of this had to do with the fact that oseltamivir is not approved for use in children in Japan, the home of baloxavir's manufacturer and of many of the children in the study.)
4. When looking just at amounts of influenza virus being shed in the respiratory tract, baloxavir decreased the viral quantity much more quickly than did oseltamivir but as stated in #1 above with no substantial clinical benefit.
5. Side effects attributable to baloxavir weren't bad, mostly GI, about 4%.
6. Most of the influenza viruses infecting study subjects were influenza A, so we don't know much about how baloxavir will handle influenza B virus infection.
7. Baloxavir resistance developed in some recipients on therapy, a cautionary note for the future. However, another study published this summer showed that those baloxavir-resistant mutant flu strains did not replicate well in tissue culture, implying they may have lost virulence with this resistance mutation.

So, what would I recommend for now?
- The main down side of baloxivir is that it is new, too early to know about very uncommon or rare side effects as well as how well it will perform in real life where we don't always have the opportunity to start treatment in the first 48 hours of illness. Also note that the number of pediatric age group subjects studied was very small.
- I wouldn't use it all under 12 years of age, we have no data in that age group.
- Baloxir is easier to use than oseltamivir - 1 dose versus 2 daily doses for 5 days with oseltamivir. That could be important for some of your patients and families.
- The part about faster decrease in viral quantity in respiratory secretions in #4 above might be a consideration if your patient is in a household or otherwise in close contact with an immunocompromised/high risk patient. Although not really studied, it's possible that the decrease in viral load might translate to a shorter duration of transmissibility of live virus to others.

Oh, and by the way, baloxivir is being estimated to cost $150 (allegedly with a coupon available in the US to bring it down to $30 for insured individuals), compared to about $135 for oseltamivir, but again oseltamivir coupons are available online and elsewhere. Of course everything varies according to insurance plan, so maybe best to recommend that individuals check with their own plans about both drugs. All other things being equal on the risk/benefit scale, I'd go with whatever is cheaper.

*Actually the correct term is Priority Review, a process set in place by the 1992 Prescription Drug User Fee Act (PDUFA) where pharmaceutical companies pay a user fee to the FDA. Under Priority Review, the FDA reviews an application within 6 months rather than the usual 10 months under Standard Review, partially funded by these fees. A drug manufacturer can request a Priority Review, but the FDA determines if it is appropriate and uses the same criteria for approval that are applied under Standard Review.

At the Montgomery County Pediatric Society's first meeting of the year this past week, Dr. Kirsten Hawkins, chief of adolescent medicine and residency program director at Georgetown University, presented a very engaging discussion on hot topics in adolescent health. Of course I was particularly drawn to her mention of adolescent immunization and thought I'd expand a bit on some of the points she mentioned.

First, a bit of encouragement about successes with human papillomavirus (HPV) vaccine down under. A recent computer modeling study estimated dramatic decreases in cervical cancer rates in Australia related to high vaccine uptake and screening programs in that country. In 2016 it was estimated that just over 78% of 15 year-old girls and 72% of boys had received the full course of 3 doses of quadrivalent vaccine. (Subsequently recommendations changed to a 2-dose regimen with the nonavalent vaccine.) Mathematical modeling presented in the article predicts that fewer than 4 per 100,000 Australian women will be diagnosed with cervical cancer annually by the year 2028, a threshold below what is generally accepted as a "rare" cancer. Contrast that with rates for US teenagers, where a little under 50% were fully immunized against HPV.

Dr. Hawkins also mentioned the meningococcal B vaccine, including a key point that meningococcal epidemiology differs significantly by country. In particular, group B meningococcal disease is much more common in the United Kingdom compared to the US, so meningococcal B vaccine is more cost effective in that country compared to the US. (Keep that in mind if any of your adolescent patients attend college in the UK.)

Certainly adolescents attending college in the US are at somewhat higher risk for group B meningococcal disease than are US adolescents not attending college, but the risk is still so low that universal meningococcal B immunization is not cost-effective. Also weighing into this equation is that not all meningococcal B strains are the same, and meningococcal B vaccines have varying abilities to protect against infection with different bacterial strains. So, meningococcal B vaccines are an option for healthy adolescents, but universal meningococcal B immunization is unlikely to significantly alter the epidemiology of this disease. Remember that the 2 meningococcal vaccines are not interchangeable, once a child has been immunized with 1 product you must use the same product to complete the full vaccine series. Take this opportunity to review the CDC's resources on the topic.

Today's Morbidity and Mortality Weekly Report contained updates on the flu season just past. First of all, the report confirms what we already knew, that it was a fairly busy season. Pediatric deaths were high, total of 171 influenza-related deaths have been confirmed. When I looked back, this number is similar to the 2014-15 flu season. Sadly, of those fatal cases who would have been eligible to receive flu vaccine, only 22% had received at least 1 dose of vaccine. That's a real missed opportunity, since flu vaccine is significantly effective in preventing more severe illness.

Unusual for the season just ended was the fact that the severity of illness was high for all age groups, the first time that particular scenario has been noted since the CDC has applied new definitions for flu severity now dating back to 2003-4:

On another note, those of you who attended the most recent Montgomery County Pediatric Society meeting may recall my answer to an audience question about whether to use the new live attenuated influenza vaccine (LAIV4, aka FluMist) recently approved by FDA. You recall the previous iteration of this vaccine was removed from the market due to poor efficacy, particularly against the H1N1 2009 pandemic strain.

The newer product appears to produce higher antibody levels, but that's not the same as whether it has better efficacy; we will only know that when we see how it performs in the real world, in a year when we have more H1N1 activity than we had this past year.

The Advisory Council for Immunization Practice officially does not designate a preference for any of the types of flu vaccine over another. My response at the May meeting was that I wouldn't use it for my family members, and perhaps only to consider ordering it if you felt that you had families in your practice that would refuse the inactivated (injectable) vaccine; LAIV4 is better than no flu vaccine at all. It turns out my advice is more in keeping with AAP recommendations, now advising using LAIV4 as a "last resort."

This week's Morbidity and Mortality Weekly Report had a timely article summarizing outbreaks associated with treated recreational water over the time period 2000 - 2014. I'll share a few take home points.

A total of 493 outbreaks were reported over this time period, and 363 (74%) had a confirmed infectious etiology. Any guesses as to the number 1 identified infectious cause? If you said Cryptosporidium, you win the prize. Second place wasn't even close, more or less a tie between Legionella and Pseudomonas, with the latter manifest mostly by folliculitis and otitis externa. Hotels were implicated in about 1/3 of the outbreaks.

The report included a little informational poster with some fairly obvious but still important messages to the public:
1. Don't swim with diarrhea
2. Check the pool or hot tub inspection score (more on this below)
3. Don't swallow the water

I had never really looked into how public pools or hot tubs were regulated, but not surprisingly there are rules governing this with oversight by county/state health departments. I decided to try to find out pool inspection scores for some area hotels, and I had a lot of difficulty. Montgomery County Health Department's web page listed a bunch of regulations, but I couldn't see anything there about individual hotel reports. Needless to say, going to a hotel's website isn't likely to help anyone find out when the pool was last inspected, or how it scored. This seems to be true for most of the country. So, I guess if you're really concerned about your vacation spot's pool or hot tub health rating, you'd need to ask the hotel specifically. The CDC does help if you wanted to look at the sites responsible for outbreaks in the past, via this site.

My only swimming possibility this summer is a lake, not covered by the treated recreational water regulations. I'll just have to take my chances.

Tried any kratom? Now wouldn't be a good time to do so.

If you are like me, you're not familiar with kratom. I actually heard about it almost 2 years ago, in a CDC blurb about poisonings and overdoses with the substance. Now, however, it's associated with a new public health danger, salmonellosis due to S. Javiana, S. Okatie, and S. Thompson serotypes. CDC first publicized the outbreak last month, with illness onset as early as October 2017. Now, however, the outbreak is expanding to a total of 87 people in 35 states. The most recent states added including Maryland and West Virginia. Take a look at the current case count map.

Kratom's other name is Mitrabyna speciosa, a cousin of the coffee plant. It appears to be used as both a "natural" remedy as well as for recreational purposes for its opioid- and stimulant-like effects. If you happen to uncover any cases of salmonellosis, be sure to ask about kratom exposure. Also, at this time there is no common source supplier of the tainted kratom, so CDC is advising to avoid all use of this compound. (Not that anyone should be using it anyway!)