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October 28th, 2018

New Flu Drug Offers Convenience, Fast Activity, and a Novel Mechanism — at a Price

National Library of Medicine

Last week, the FDA approved a new drug for treatment of influenza, baloxavir marboxil (Xofluza).

The drug is indicated for treatment of symptomatic influenza in patients 12 years of age or older. As with existing treatments, it should be started within 48 hours of symptom onset.

In a comparative clinical trial in otherwise healthy outpatients, baloxavir and oseltamivir (commonly known as Tamiflu) comparably reduced the duration of flu symptoms — both on average by about 36 hours. Each treatment was more effective if started within 24 hours of symptom onset.

Baloxavir differs from oseltamivir in several ways, some of them potentially important:

  • Treatment is a single dose. Patients receive 40 mg if their weight is between 40 and 80 kg, and 80 mg (two pills) if 80 kg or more. As every primary care clinician knows, oseltamivir is 75 mg twice daily for 5 days.
  • Side effects ascribed to the treatment occurred less frequently in those randomized to baloxavir vs oseltamivir — specifically, 3.9% and 8.4% for baloxavir and oseltamivir, respectively (p=0.009). The side effects table from the study indicate that GI-related side effects (especially nausea) were numerically more common with oseltamivir. In clinical practice, this is the most commonly encountered problem with the drug, which can be diminished (but not eliminated) when oseltamivir is taken with food. The incidence of severe adverse events did not differ between arms.
  • Baloxavir lowered influenza viral loads in respiratory secretions faster than oseltamivir. The clinical significance of this faster antiviral action is unclear. Might this make patients less contagious more quickly? Or could this translate to a clinical benefit in very immunocompromised hosts, or in the most severe cases? A study in “high risk” adults demonstrated a faster recovery time compared to oseltamivir if the infecting virus was influenza B; outcomes in influenza A were similar. A different clinical trial of the drug in hospitalized patients is about to start.
  • The mechanism of action is different. Unlike the neuraminidase inhibitors (oseltamivir, et al), baloxavir blocks influenza replication through inhibition of viral endonuclease (see the fine video below). It’s the first flu drug with this mechanism of action. The good news is that baloxavir should retain activity against neuraminidase-resistant strains, which periodically emerge and could be a substantial global threat.
  • Baloxavir treatment selects for resistance. This excellent accompanying editorial to the above-cited phase 3 trial describes the resistance concerns in more detail. Will this resistance limit the usefulness of the drug? Or will the impaired replication capacity of resistance variants make them less transmissible?
  • Oseltamivir is generic, and cheap. A 5-day course costs around $50. Payers have undoubtedly negotiated a much lower price. (That stuff is kept secret from us patients and clinicians, remember.) Baloxavir will cost $150, regardless of the dose, with coupons available to lower the price.

My colleague Ken Freedberg, whose research focus is cost-effectiveness, often jokes that he’s frequently the last to speak at a conference since the topic of cost is so often considered secondary to the “scientific” parts of the program.

Please note, Ken, that I meant no offense by putting cost last in the bulleted list above.

Especially since with baloxavir, it’s probably this very point — cost — that will limit use of the drug, at least initially. Insurance plans are not eager (an understatement) to add new treatments to their formularies that cost more than existing options unless they are clearly more effective, or safer, or preferably both.

With baloxavir, while it seems to have some advantages over osteltamivir in these metrics, we’re not quite there yet.

In the meantime, we can make fun of the brand name —Xofluza! — which, if you say it loudly and quickly, kind of sounds like someone sneezing.

October 21st, 2018

A Day in the Life of the Academic Assistant Professor of Medicine Who Wakes Up at 5:30 a.m. to Get Her Kids to School, Takes the Bus to Work, Answers Emails, Completes Online Required Modules, and Fills Out Disability Forms for Her Patients

(Inspired by a recent peculiar article about a Bay Area tech superstar.)

Dr. Camilla Gormley is always on the move.

From the moment her alarm wakes her at 5:30 a.m. to prepare breakfast and school lunches for her three kids, to the time 16-plus hours later when she can finally rest her head on her pillow, Dr. Gormley is constantly in motion.

On a typical day, after bundling up her kids to be dropped off at school by her husband Jack — if he’s not traveling for work, in which case she (somehow) has to do it — she can be seen running after the bus which, on a good day, will have an available seat and not smell like last night’s frat party.

She recently shared with us the rhythms and rewards of being a Junior Faculty member at a prestigious academic medical center.

5:30 a.m.: She wakes up and immediately panics that she has forgotten an important deadline.

“I find that this early time of day is perfect for free-ranging anxiety and panic,” says Gormley. “It’s a tremendous relief when I realize that I don’t in fact have a school paper due, or an exam today — though one of my three kids might.”

The first task for the day is feeding her family, which consists of a streamlined operation that efficiently generates five breakfasts, two coffees, and four bagged lunches. Husband Jack takes orders and has learned the hard way not to talk back.

“He once expressed doubts about my selection of bread for the kids’ sandwiches,” she recalls. “He found himself alone on food duty for the next month, which was a disaster for all. But that will teach him.”

6:30 a.m.: She wakes her kids and helps them get dressed and ready for the day.

“My son Zack will wear anything, he’s easy,” she says proudly. “Same with Jenna, the youngest.”

But, she notes, middle child Phoebe can be a challenge. “Not a week passes by without her wanting some crazy new style to wear, nothing’s ever right,” she says. “We’re at the point where if she told me she wanted to wear her bathing suit to school in the middle of winter, I’d just give in. Sick of it, really.”

7:00 a.m.: Dr. Gormley gets in some intense cardio by running for the bus.

“If I miss the 7:05 — which stops right at our corner — I’ll never make it to work in time for my 8 a.m. patient.”

She spends the time on the bus catching up on emails that were sent overnight.

She shares one request: “Can we outlaw the ‘high importance’ exclamation mark in emails, please?” she asks. “And people who use that for emails sent overnight should be imprisoned.”

8:25: Her 8 o’clock patient shows up — as does her 8:30.

“Of course, I saw her anyway,” she said, of her late-arriving patient. “And she had a disability form for me to fill out — putting my MD degree to work!”

It’s fall, so it’s flu shots for everyone — except the patient who refused, saying it always gave him the flu.

“Oh, give me a break,” she editorializes.

12:45 p.m.: After seeing her outpatients, she paused for a quick lunch at her desk — but didn’t stop working.

“You know those corporate lunches in Mad Men, with martinis and glamorous companions in Manhattan restaurants?” she asks.

“My companion is my office computer with a required online video about fire safety.”

1 p.m.: Time to check the electronic “inbox” on her electronic medical record!

“Usually the in box has another couple of hours of work in there, at least,” she says.

“I feel like the EMR inbox should have a sign that says, Open at Your Own Risk, or Ye Who Enter Here, Abandon All Hope.

3 p.m.: Dr. Gormley attends a meeting about the medical school course she’s teaching in the fall. The meeting is in a conference room half a mile away, so she debates whether to walk or to Uber — she’s so undecided that she arrives 15 minutes late, as does almost everyone else.

“Teaching in this course is awesome,” she says. “But why are all the meetings held so far from the hospital?”

Also not so great — deadlines for submission of PowerPoint slides and the dreaded requirement for “learning objectives.”

“Has there ever been a study showing that submitting ‘learning objectives’ actually led to more learning?” she wonders. “What if I just ignore the request?” she says, a sly smile creeping over her face.

4 p.m.: She’s back in her office, poring over emails that have accumulated since she last had a moment to check.

“Let’s see, there are 58 messages here,” she notes. “I think I’ll do the ones marked as ‘high importance’ last, just for revenge.”

Included in the email barrage are several invitations to bogus medical conferences (“Greetings of the day!” they begin), as well as sales pitches for laboratory reagents, monoclonal antibodies, and small rodents.

“Why do I get emails asking if I want reagents for doing my own CRISPR experiments or for a supply of knockout mice?” she asks. “That reminds me, I need to call the exterminator for the ant problem we have at home.”

She also receives a dire warning — yes, ‘high importance’ exclamation point — that the annual Conflict of Interest form (required of all faculty) is overdue.

5:45 p.m.: As a big believer in never wasting a single moment, Dr. Gormley starts the online Conflict of Interest form on her phone while waiting outside for the bus.

“Last week I started it three times and it kept crashing,” she says.

“Apparently, if you do it at your computer, you need to be running Internet Explorer. Internet Explorer! I mean, could they please start using a browser that is updated for this century? Is that so much to ask?”

Completing the form takes her approximately 30 minutes, which completely ends all hope of listening to that great podcast everyone has been talking about, whatever it’s called.

6:30 p.m.: She arrives home to find that her three kids are fighting, their cat Quentin has vomited on the rug, and that her husband has forgotten it’s his night to plan dinner.

“I give him one thing to do,” she sighs. “Am I the only one who thinks that families need to eat to survive? You didn’t need to go to medical school to learn that.”

She picks up her phone and dials the local Mexican restaurant, which delivers.

While waiting, she and her husband reflect upon their key wins and challenges and prepare for the adventures of the next day.

“Just kidding. We’re just trying to survive here.”

7:00 p.m.: Take-out burritos for everyone.

“It’s only the third time this week,” she says, defensively.

(It’s Thursday.)

7:30–9:30 p.m.: Gormley and husband Jack help all three of their children with homework, then Gormley starts laying out their kids’ clothes for the next day.

“If Phoebe says one thing about the clothes I put out for her, there might be Armageddon,” she says.

9:30 p.m.: As she’s washing up for bed, she remembers that she forgot to call the exterminator, and adds it to tomorrow’s to-do list.

“Ants aren’t so bad,” she rationalizes.

With thanks to Carolyn Frank Sax, MD, who really did have a cat named Quentin.

October 15th, 2018

Outpatient Antibiotic Prescribing Boosts Patient Satisfaction Scores, Rewarding Bad Medical Practice

A recent study confirms what every busy clinician already knows.

Many patients seeking care for respiratory infections expect to receive an antibiotic. When they get one, they’re happier than if they don’t.

Among 8437 patients seeking care for a respiratory tract infection in a direct-to-consumer telemedicine service, 66% received an antibiotic. The rate of prescriptions prescribed by physicians ranged from 19% to 90%, showing that these were not exactly evidence-based decisions. Satisfaction ratings strongly correlated with adjusted antibiotic prescribing rates (Pearson correlation, 0.41; P < .001).

It’s even worse if you look at the figure — none of the MDs in the lowest half of prescribers exceeded the 75th percentile for patient satisfaction.

More details:

Few physicians achieved even the 50th percentile of satisfaction while maintaining low rates of antibiotic prescribing. To reach the top quartile, a physician had to prescribe antibiotics at least half the time; almost all physicians above the 90th percentile had a rate of antibiotic prescribing greater than 75%.

This isn’t the first time we’ve seen data like these. In this earlier study comparing immediate versus deferred versus no antibiotic (along with a patient education intervention), patients with the immediate antibiotic prescription were significantly more likely to be very satisfied with their care — even though clinical outcomes were, not surprisingly, the same.

Jeffrey Linder — who studies appropriate outpatient antibiotic prescribing — would no doubt remind me that not every study demonstrates this effect of antibiotic prescribing and increased patient satisfaction. While this is true, his group just presented data that many antibiotic prescriptions aren’t written in the context of a patient visit, and often for diagnoses not even related to infection.

I asked a physician who works with one of the companies charged with assessing patient satisfaction what he thought about these recent survey data. He made the excellent point that it was physician communication — time spent talking with patients — that most powerfully drove patient satisfaction.

While no doubt this is true, let’s imagine you control for this talk-time. And that clinicians in urgent care centers and telemedicine systems are graded on volume (productivity) and patient satisfaction scores. Some would undoubtedly consider the counseling and education piece too time consuming. Remember, it was urgent care centers that had the highest rate of inappropriate antibiotic prescribing in a study published earlier this year.

What’s the fastest way for urgent care and telemedicine clinicians to achieve higher scores in patient satisfaction and “see” more patients/hour? In our action-driven society,  it’s doing “something” (antibiotics, pain relievers, sleep aids, MRIs, you name it) rather than “nothing” (observation). It takes energy and time to explain why the latter is often the right choice.

If you doubt my ID-doctor biased perspective, here’s another interesting view on this study from F. Perry Wilson on Medscape:

All of this  leads to an all-too-familiar patient encounter, typified by this note from a local walk-in center:

Finally, could anything comment more appropriately on this relationship between antibiotics and patient satisfaction than this New Yorker cartoon?

So what are we going to do about it?

October 8th, 2018

“Mini”-Really Rapid Review — IDWeek 2018, San Francisco

This is a very valuable pear.

Once upon a time, the annual meeting of the Infectious Diseases Society of America (IDSA) wasn’t much of a research conference.

It consisted mostly of review sessions on topics deemed worthy of an update or a refresher, led by noted experts in the field. They would cite the latest literature on endocarditis, or mycoplasma, or prosthetic joint infections, or malaria, or transplant infections, or HIV complications, or sternotomy infections following cardiac surgery.

(I kid you not about that last one … to each their own, I guess!)

Some of this was good stuff — cutting edge and exciting — but some was frankly kind of tedious. You went because it was “good for you”, kind of like eating kale if you don’t like kale.

And pretty much all of it was led by white men of a certain age — which is my age now, give or take a decade, good grief.

My, how times have changed, and emphatically for the better.

The IDSA meeting, re-branded “IDWeek” a few years ago, now mixes in original research with not only these terrific review sessions (you can still skip the one on sternotomy infections), but also challenging case presentations, entertaining debates, policy updates, and awards.

Importantly, presenters, participants, and awardees all increasingly reflect the diversity of our field, making the meeting feel much more inviting and collegial — a very welcome change.

There’s so much going on no one can cover it all, certainly not me. So here’s a sampling of some (emphasis on some) of the interesting research presentations from last week, a “Mini” Really Rapid Review™ of the conference. Use the comments section to chime in with your favorites.

There was plenty more, of course — read the many responses to this query!

As for the pear, it cost a staggering $4.64 in my hotel lobby. Remember when San Francisco was affordable? I don’t either.

At least I saved money on the flight out there.

October 2nd, 2018

Winner of Latest Cartoon Contest Proves Again That We ID Specialists Are a Different Breed

It is with a mixture of professional pride and embarrassment that I hereby present the winner of our last ID Cartoon Caption Contest:

“You have Listeria meningitis.”

Yikes. Talk about inside jokes.

Though the second-place finisher “Ah, no, I prescribed the AEROSOLIZED, not PARASOL-ized form” mounted a late charge, the geeky reference to Listeria monocytogenes and its “umbrella motility” held out for the win.

Let’s pause for a moment to consider the sheer obscurity of this winning caption:

Ha ha!

Special thanks to Sébastien Poulin for being the first to submit it, and doing so all the way from Canada. That couldn’t have been easy, what with the latest controversies in US-Canada relations.

As is customary, Sebastien will receive a lifetime free subscription to this blog. Perhaps he’ll even come this week to the annual gathering of ID nerds like him in San Francisco to pick up his prize.

Not surprisingly, the caption completely baffled my sister Anne, creator of the above cartoon (and not an ID doctor). She had no idea she was going to elicit listeria associations with her skillful and silly drawing. Our astute editors at NEJM Journal Watch were similarly perplexed, but too embarrassed to ask me to explain the joke.

(Now do you get it?)

While we’re all enjoying that bit of ID-related humor — and we are, aren’t we? — allow me to share this spot-on parody of how we ID doctors can obsess over obscure details (like umbrella motility) when sometimes those consulting us just want to know what to do:

For the record, that’s Brown medical resident Zoe Weiss, poking affectionate fun at her revered ID attending Dimitrios Farmakiotis.

(All “actors” gave permission to post this video, by the way. Send the lawyers away.)

And since Zoe made the best possible choice when it comes to her upcoming subspecialty training (ID, of course), she will one day play the same important role as Dimitrios — lecturing, um I mean teaching, impressionable residents.

Hope to see you at IDWeek!

September 23rd, 2018

Picking Your Next ID Journal Club Paper? MERINO or POET Trial? Two ID Fellows Debate

Late afternoon/early evening at an academic medical center. Bright young doctors sit in a hospital workroom, putting the finishing touches on what are undoubtedly the most comprehensive and, yes, simply the best consult notes in their respective patient’s electronic medical records. 

Best ever.

ID Fellow #1:  Hey, pretty soon we have to do Journal Club, right?

ID Fellow #2:  Yep, coming up. And you’re first! And I’m the following week. Most important question — do they feed us at these conferences?

ID Fellow #1:  Not sure — this is one of the hardest things about fellowship. You never can tell when there’s food. During residency, there was always food.

ID Fellow #2:  Agree, big drop off. That food issue and late afternoon consults might be the hardest thing about this year.

A bit more work is done on their respective masterpieces — one a 2000-word opus summarizing a 6-week hospitalization involving several surgeries and a prolonged ICU stay, the other a 9-year history of recurrent lower extremity ulcers in a diabetic with vascular disease.

ID Fellow #1:  I think I’m going to choose the MERINO trial — piperacillin-tazobactam [he didn’t really say “piperacillin-tazobactam,” but used the Z-word, alas] vs. meropenem in ceftriaxone-resistant [mostly ESBL] bacteremia. Mero was better! Great to have a definitive result.

ID Fellow #2 (somewhat warily, since obviously she was going to pick the same paper):  Yes, meropenem was better, but not superior — in other words, pip-tazo was not demonstrated to be noninferior to mero in the primary endpoint, which was all-cause mortality at 30 days after randomization. (Sensing weakness.) You sure you have the statistical chops to discuss this?

ID Fellow #1 (clearly wavering):  Erm … not sure. So not noninferior? Yikes, that double negative is confusing. But it will give me a chance to review the purpose of noninferiority studies. I remember in my med school stats class, one of my favorite teachers said we should replace “noninferior” with “Not too much worse than …” Always liked that. You know, real English.

ID Fellow #2 (thinking that MERINO is now taken, so might as well be generous with her knowledge):  Hey, if you really want to get down the statistical rabbit hole in MERINO, there’s a great review I read online about it — I can text you the link. Plus, the investigators amazingly did a really interesting thread on Twitter, answering some of the most common questions they’ve been getting. How great is it that?

ID Fellow #1 (sensing that he may be out of his league on MERINO):  OK … maybe you should do MERINO. I was also thinking of the POET trial — IV vs. oral antibiotics for endocarditis. Oral was noninferior. Highly relevant, and I still get to show off by discussing noninferiority trials.

ID Fellow #2 (delighted that she now has MERINO back):  Great choice! Could be “practice-changing”; always good to cover a study where you can bring out that powerful phrase. Plus, no gels or blots or GWAS to explain.

ID Fellow #1:  Yep, it’s a great study. But I do have some issues. The eligible patients had to receive at least 10 days of IV therapy before randomization — why 10 days?

ID Fellow #2:  Follows the rules.

ID Fellow #1:  Amazingly, there was no MRSA! And only around 1% had injection drug use as a risk factor — both limit generalizability. Plus, the oral regimens are weird. Fusidic acid? What the [word unintelligible] is that? And putting the drugs used in the supplementary appendix was a bizarre decision, almost like they were trying to hide something. You can tell it was presented at a cardiology and not an ID meeting. We’d never tolerate that.

ID Fellow #2 (worried he might go back and take MERINO): So are you saying you don’t like the study?

ID Fellow #1:  No, I think it’s great — imagine how many fewer vanco levels we’d need to chase if PO antibiotics became standard of care for endocarditis! It’s just not perfect. But it’s the exact sort of study we should see more often. It asks an important clinical question, and answers it.

ID Fellow #2:  You mean like oral vs. IV antibiotics for osteomyelitis?

ID Fellow #1:  Exactly! Hey, what happened to that study?

They go back to putting the finishing touches on their notes. The signed notes get transmitted electronically to an ID attending — who feels deep gratitude about working with such a smart and dedicated bunch, believe me.

September 16th, 2018

Supermarket Chain CEO Defends High Prices of Water, Salt, and Other Items as a “Moral” Requirement

Inspired by recent events in antibiotic pricing.

SACRAMENTO, CA. The head of a national supermarket chain is defending a recent substantial increase in the price of water, salt, and other food and kitchen essentials, arguing that this change is the equivalent of a “moral” requirement.

Last month, iFoods Plus Stores announced that common low-cost items such as water, salt, paper towels, and carrots would all have major price increases.

A 12-oz plastic cup of tap water at the food counter will increase from $0.25 to $2.50, and a 26-ounce container of salt will now sell for $6.99 rather than $0.99. A package of two rolls of paper towels will set a purchaser back $19.99, 10 times up from its previous price of $1.99.

Citing occasional price increase from Whole Foods, Trader Joe’s, Walmart, and other food sellers, iFoods Plus CEO Jack Stevenson said his store’s price increases were not only essential to maintain profits, but were “morally the right thing to do.”

“Our first priority is our shareholders,” said Stevenson. “We live in a capitalist system, and not to take advantage of opportunities to hike prices in settings where we have little competition would be ethically wrong.”

When pressed, he added “Our customers’ well-being and comfort are also important,” but was unable to explain what he meant by that statement.

Some of the price increases have raised concerns among iFoods Plus shoppers, many of whom rely on the stores since the company favors locations with few or no other market options.

And consumer groups say that the increases are unjustified, since most of these items have long been available, and do not represent innovation or research done by the company.

“Water consists of two hydrogen atoms and one oxygen atom, and is considered an essential building block of life on earth,” said Karen Hartfield, head of a food pricing watchdog group. “iFoods Plus did no research and spent no money developing the product. They just get water from the tap.”

Hartfield went on to say that salt, or sodium chloride, is a commonly used household flavoring. In general use long before the beginning of recorded history, salt has been off-patent internationally since 2700 B.C., when generic companies used Chinese pharmaceutical treatises to make salt from seawater.

“Paper towels are, well, just paper,” she said.

In the most dramatic example of skyrocketing prices at iFoods Plus, a one-pound bag of baby carrots, previously $1.99, is now listed at $99.99 — a 5000% increase.

“These carrots are very popular, and quite delicious,” noted CEO Stevenson, “So I’m just charging what the market can bear.”

He further acknowledged inspiration by another company that pulled off a similar price hike. “That man was a genius, and clearly schooled in high-level ethics and moral thought.”

Stevenson also said the price of the small bag of carrots would be reduced to $59.99 with a special Customer Assistance Program. Eligibility criteria include demonstration of vitamin A deficiency, or genetic testing indicating that a person is part rabbit.

Note — in case you didn’t know that there were no patent laws in 2700 B.C., this is satire.

September 9th, 2018

Doravirine Sets a New Standard for NNRTIs — But What Role in HIV Treatment Today?

“Hello, we are Pifeltro and Delstrigo.”

The HIV drug class called “non-nucleoside reverse transcriptase inhibitors,” or NNRTIs, must have something of an inferiority complex.

First, anything defined by what it is not is already in trouble. Believe me, hepatitis C was thrilled when it could shed the “non-A, non-B hepatitis” label.

Second, despite their high antiviral potency and good tolerability, the NNRTIs have always been an afterthought to the protease inhibitors (PIs) when discussing how combination therapy transformed the effectiveness of HIV therapy back in the 1990s. Take a look at this classic paper — over 5000 citations and counting — especially its famous figure.

However, from a global perspective, it has been NNRTI (not PI)-based regimens in that have had the greatest impact in years of life saved from antiretroviral therapy.

Let’s add to the NNRTI list of accomplishments by citing that no study of initial therapy has ever demonstrated superiority over efavirenz from a purely virologic perspective (not even dolutegravir); that a meta-analysis did not show a difference in clinical outcomes between PI and NNRTI-based therapies; and that efavirenz-based regimens appear (ironically) to be quite safe for the fetus during conception and pregnancy.

So — now that I’ve defended the drug class, let’s introduce the latest member, doravirine, which was approved by the FDA during their busy last week of August.

Approval of both doravirine individually and the coformulated doravirine/lamivudine/tenofovir DF tablet was based on the results of two clinical trials.

Given with TDF/FTC or ABC/3TC, doravirine was non-inferior to darunavir + ritonavir with a better lipid profile at 48 weeks, and superior at 96 weeks due to fewer adverse events. Similarly, the once-daily single tablet was compared to TDF/FTC/EFV in a double-blind trial, and also found to be non-inferior.

Dosed 100 mg once-daily, doravirine has several advantages over existing drugs in the NNRTI class:

  • Few drug interactions, in particular none with acid-reducing agents.
  • Can be taken with or without food.
  • A more favorable lipid profile, lower incidence of rash, and fewer CNS side effects than efavirenz.
  • A novel resistance pathway, with activity against viruses with K103N or Y181C mutations. By contrast, the V106I and F227C mutations selected by doravirine do not cause in vitro resistance to either rilpivirine or etravirine — and may induce hypersusceptibility to certain NRTIs.

These advantages notwithstanding, the role of doravirine or the coformulated tablet in HIV treatment today is uncertain. Major HIV treatment guidelines now list integrase inhibitor based regimens as preferred for initial therapy, and the drug has not been compared to an integrase inhibitor in any clinical trial. Furthermore, the single tablet option contains tenofovir disoproxil fumarate, which has more renal and bone toxicity than tenofovir alafenamide.

Still, since this appears to be a “best in class” drug, doravirine has enough advantages that it is a useful advance in HIV therapy, if not a transformational one. Think of the following patients, for example:

  • Those who can’t tolerate integrase inhibitors.
  • Someone looking for efavirenz or rilpivirine alternatives within the same drug class, due to concerns over CNS side effects or use of acid-reducing agents, respectively.
  • Off-label use as part of a switch strategy for patients with susceptible virus. (A switch study is ongoing.)
  • As a cost-saving strategy, depending on listed and negotiated prices — in particular for the single tablet, since the non-doravirine components are generic.

Of note, doravirine is also under study with the potent and long-acting agent MK-8591 as part of a two-drug strategy. MK-8591 is an NRTTI, the second T standing for “translocation”.

Two final points: The drug is abbreviated “DOR” — not “DRV,” which was already taken by darunavir.

And the brand names are Pifeltro, for doravirine alone, and Delstrigo, for the coformulated single tablet — note that “STR” in there? One can assume that stands for “single tablet regimen.”

Still, together they sound like the name of a famous Sicilian puppet duo, best known for their slapstick comedy routines.

September 3rd, 2018

Eravacycline Approved by FDA — How Might It Be Used, Today and in the Future?

WPA Recreation Project, 1939

While last week the world was sunning on the beach, hiking in the woods, eating ice cream, and performing careful tick-checks, the hard workers at the Food and Drug Administration hunkered down in Silver Spring, Maryland to get three anti-infectives approved — eravacycline, doravirine, and doravirine/TDF/3TC.

Maybe they saw the weather reports — hot and humid, this is the D.C. area! — and figured they might as well stay inside. Take advantage of the climate control and finish off these applications!

Let’s consider the antibiotic approval first.

As the name suggests, eravacycline is a tetracycline derivative, but with a much broader antibacterial spectrum. This includes many highly resistant gram negatives (including some carbapenem-resistant organisms and acinetobacter), MRSA, VRE, and anaerobes. Pseudomonas aeruginosa is an important exception to its broad coverage.

The drug’s approval was based primarily on clinical trials demonstrating non-inferiority to ertapenem in intra-abdominal infections, and a second study versus meropenem with similar results — hence this is the indication in the label. Treatment for complicated UTIs vs levofloxacin didn’t go well, so the drug is not recommended for UTIs. Because eravacycline is hepatically metabolized, there’s no need for dose-adjustment in renal failure.

As with tigecycline (to which one inevitably draws parallels), gastrointestinal side effects predominate, though appear to be less common — good news, since nausea is far and away the most common dose-limiting side effect for tigecycline. Infusion site reactions are more common than with the carbapenems.

Encouragingly, the company plans to price the new drug at the lower end for a recently approved antimicrobial, bucking a common trend for new drugs.

So we have this new antibiotic — how will it be used?

To echo a common refrain of most recently approved agents, eravacycline will not immediately be a first-line option for its approved indication, intra-abdominal infections.

However, if we get a bit creative, one could envision an important role for eravacycline in certain patient scenarios — with the caveat that some are admittedly speculative and definitely off-label.

Roughly in order of plausibility (most to least), here are several potential treatment settings for eravacycline:

  • If tolerability is confirmed in clinical practice to be better than tigecycline, in place of that often troublesome drug.
  • In a patient with intra-abdominal infection, documented allergy to beta lactams, and known to harbor fluoroquinolone-resistant organisms.
  • For someone at very high C. diff risk — especially if eravacycline proves to be as low risk as other tetracycline-class drugs.
  • In therapy of ceftriaxone-resistant gonorrhea — this will need a clinical trial, of course, to establish efficacy and dose.
  • For treatment of non-tuberculous mycobacteria, in particular M. abscessus — but first it would be optimal to see in vitro activity, and preferably approval of the oral formulation (regardless of what it’s approved for).

As for the brand name, Xerava — is it just me, or is this a trap for a drug name mix-up?

I’m thinking, of course, of a very widely used oral anticoagulant!

August 23rd, 2018

Eye Worm, MALDI-TOF, New Lyme Testing Approach, Dogs Fail as C. diff Testers, Uiyk (?), and More — A Summer Is Getting Shorter ID Link-o-Rama

Ben Taylor (aka Mometo) (1970–), The Host (2014). Cover of Emerging Infectious Diseases, August 2018

A recent chilly spell here in Boston recalled a universal truth about aging — that summer seems to get shorter every year.

As far as I can tell in my unscientific poll of everyone who will engage with me on this topic, there are no exceptions to this rule. Everyone thinks summer is shorter than when they were kids, even though the calendar says summer lasts around 90 days — every year.

Why is the sun going down so soon? Is it already mid-August? No more free summer weekends? Didn’t it just get warm? Winter coats in catalogs? Back-to-school specials at the office supply stores? Halloween costumes at Costco? Summer is over already???? ARGHHHH!!!!

On to an ID Link-o-Rama, this one designed to accompany the late afternoon slanting sunlight that seems to say, “Too soon, too soon.”

  • Ibalizumab is effective in patients with multi-drug resistant HIV. This humanized IgG4 monoclonal antibody blocks viral entry, and is given as an infusion every two weeks. Notably, drug development of ibalizumab started around two decades ago, when we had many patients who could not achieve virologic suppression because of  resistance — a situation uncommon today. That a phase III trial had only 31 patients and that the FDA approved it anyway demonstrates two things: 1) There are very few people who need this drug; 2) those who do need it really really need it — it can be life-saving. Trivia question — why is it called “ibalizumab-uiyk“?
  • There are significant knowledge gaps about TB diagnosis and treatment among medical residents. Given how rare TB cases have become in the USA — especially in certain regions — these results are unsurprising, but still important. Mandatory ID consult for cases where TB is highly suspected? Certainly would advocate consultation when the diagnosis is confirmed.
  • Fosfomycin susceptibilities are a mess. That’s the only conclusion one can draw from this interesting study of different testing methods, which highlights the difficulties of obtaining a reliable result outside of the cumbersome agar dilution method — a challenge that will become even more important when IV fosfomycin becomes available in the USA. (H/T to ID Journal Club for the link, see below for more information.)
  • It’s been quite the season for Infectious Diseases and baseball. Two cases (!) of hand, foot, and mouth disease landed separate New York pitchers (one Yankee, one Met) on the disabled list. Not only that, Cleveland outfielder Leonys Martin sounds like he had sepsis or toxic shock syndrome. Speedy recovery!

Three more items before you head back to beach.

  1. Shout out to the excellent ID Journal Club, where Dr. Nicolás Cortés-Penfield summarizes recent ID literature in clever, concise snippets. He’s been doing it for around a year — may he long have the energy to continue!
  2. On The OFID Podcast, PharmD extraordinaire Dr. Susan Davis joins me to highlight the critical role ID pharmacists play in improving patient care.
  3. On The Curbsiders Podcast, I spend a bunch of time talking about tick-related infections, in case you can’t get enough of these critters.

Hey, next week I’m on vacation — so summer can’t be over quite yet, right?

HIV Information: Author Paul Sax, M.D.

Paul E. Sax, MD

Contributing Editor

NEJM Journal Watch
Infectious Diseases

Biography | Disclosures | Summaries

Learn more about HIV and ID Observations.