Steph’s Note: This week, I’m writing about a topic that for many of you may be a “duh.” So if this is old news to you, kudos! However, for those of you (like me) who haven’t actually run into this yet - even after practicing in various (non-pediatric settings) for almost 15 years - welcome to the club of learning something new every day. Here’s how it went down…

^^Me, assessing this amoxicillin once daily script. (Image)

The Script Conundrum

I was recently at work, staffing a retail(ish) pharmacy with 4 other seasoned pharmacists. I like to think we’re a decently bright bunch with a pretty solid collective knowledge. I was commenting about the dose on a pediatric cephalexin script I was processing when one of the other pharmacists held up the hard copy of an amoxicillin script for a 4 year old that she was working on. I went over to look at it, and honestly, my brain just didn’t compute.

The script was written for amoxicillin 880mg PO once daily for 10 days.

Here’s the series of thoughts that went through my head…

What on earth is this provider doing??
880mg is higher than a usual adult dose at one time, and this kid is FOUR! I mean, I’d seen the high dose regimens of 80-90 mg/kg/day for acute otitis media, but that was still divided dosing q12h. Why is this such a high dose once a day??
Once daily for amoxicillin? It’s not XR, it’s IR.
As a beta-lactam, amoxicillin is time-dependent (not concentration-dependent). So wouldn’t dosing it lower and more frequently make more sense for achieving clinical cure?
This poor child’s stomach is going to melt with that much amoxicillin at once. Adults have a hard enough time stomaching their doses let alone this little one!
Which brought it back around to… So what the heck is this provider doing?!?? We HAVE to call, right??

Echo chambers…not so great for progress or learning… (Image)

I’m not gonna lie. I was fairly chomping at the bit to delve into a lively pharmacokinetic discussion with the provider because sometimes I really miss those interactions in my current pharmacy life. Not to mention, the other 4 pharmacists were also echo chambering with me about all of the above thoughts, so we were ready to roll.

But - and this is a big BUT - I’ve learned a thing or two about barn-storming in my years of practice, and even though my brain wasn’t jiving with the script, it did function well enough to tell me to PAUSE.

Why did my pharmacy guardian angel take over here?

Because we’re pharmacists, and we can’t know everything. Because there are often many ways to skin a cat (sorry for the idiom). Because I’ve been wrong before. And it’s a heck of a lot better to be wrong on your own computer investigating information than it is to be on rounds in a crowd or on the phone with a busy, irritated provider. Because if we’re seeing multiple scripts of the same ilk, maybe there’s something to it that I just don’t know yet.

Soooo many reasons to pause.

Rather than picking up the phone right away, I thankfully decided to be a calm, thoughtful, and resourceful pharmacist. After all, we have the internet (and all the information we could possibly ask for from a relatively simple and quick search). And that’s when I was reminded that you CAN teach an old dog new tricks. Here’s what I learned about high dose amoxicillin in pediatric patients.

The Search Strategy

As you probably learned in Pharmacy 101, I started with my tertiary drug reference, Micromedex. Because I work in a retail-ish setting, I didn’t know what the exact indication was for the amoxicillin, but I basically just started skimming all the pediatric dosing information for anything that looked vaguely like the script we had received. Lo and behold, there was an entry for amoxicillin 50 mg/kg (max 1000mg) PO once daily for 10 days under the Group A Streptococcal Pharyngitis indication.

When you refuse to give up, even when the odds are not in your favor… (Image)

Now, because I’m just not the sort to accept defeat easily, I needed to know more. Like, was it actually a legit study that got this dosing option added to Micromedex, or were we talking like 10 patients in a pharmacokinetic analysis? (I’m skeptical, what can I say.) So I checked out the reference link at the end of the dosing statement. It linked to a 2009 paper from the American Heart Association, but sadly, the link was broken. Of course.

Like a pit bull tugging on a pant leg, I persevered. I certainly wasn’t going to stop on a broken link…what if that was old info??

Now that I knew we were potentially talking strep throat as the indication, I took a slight detour to ask Dr. Google its thoughts. Upon googling “high dose amoxicillin pediatrics strep throat,” imagine my surprise when one of the first links to pop up was the CDC’s Clinical Guidance for Group A Streptococcal Pharyngitis. I was like, huh, ok that seems legit. So I clicked the link and scrolled until I found the treatment section, which listed amoxicillin dosing as such:

Now, many of you may have stopped digging here. Clearly, the once daily amoxicillin is an acceptable dosing strategy. It’s the CDC for Pete’s sake. Assuming the child in our pharmacy queue weighed ~35-40 pounds, they would fit the bill for the 880mg dose. And that’s a very reasonable weight for that age. So fill the script and get on with your life. Your work is piling up, Steph.

But nooooo, my brain is annoying and won’t let go of that pant leg until every last thread has been chewed. Instead of moving on, my annoying brain said, “Waaaaait… not only is the once daily dosing acceptable, but it’s PREFERRED?! You’re saying the lower dose twice daily is the ALTERNATE? No comprendo.” And so my digging resumed.

I figured it was time to go back to that broken link from Micromedex. That was the other viable lead here since the CDC website didn’t list any primary literature resources. So I went back to the google and typed in the name of the cited AHA paper from Micromedex, “Prevention of Rheumatic Fever and Diagnosis and Treatment of Acute Streptococcal Pharyngitis.” When I clicked the link on google…it was broken. I kid you not.

Luckily, on the AHA website, I was able to use the search box to look for “strep throat,” and the desired paper was just a few results down. Jackpot, I could finally pull the full 2009 paper. Time being of the essence, I scanned the outline for treatment options, found the bit about antibiotics, and saw that there were 4 cited articles next to the statement about once daily amoxicillin:

In comparative clinical trials, once-daily amoxicillin (50 mg/kg, maximum 1000 mg) for 10 days has been shown to be effective for GAS pharyngitis (Class I, LOE B).35–38

Yay! References 35-38. FINALLY, I was going to get the information I needed in order to fully embrace this dosing strategy!

The Amoxicillin Clinical Studies Jackpot

Study #1

First, I pulled the abstracts on references 35 and 36. Number 35 was a 1993 study from 5 Israeli family medicine clinics comparing 10 day courses of “amoxycillin” 50mg/kg once daily in children (or 750mg PO daily in adults) to “phenoxymethylpenicillin,” aka penicillin VK, 250mg PO TID or QID. One hundred and fifty-seven patients aged 3 and up were assigned 1:1 to one of the 2 antibiotics for Group A Strep pharyngitis on throat culture. Most patients (111/157) were aged 5-20 years with only 11 patients in the 0-4 year old age bracket. Clinical response rates, days lost from work/school, and persistently positive culture rates were all found to be similar between the groups. Amoxicillin actually demonstrated significantly improved bacteriologic response with no positive cultures remaining at 14 days (compared with 5 persistent positives in the penVK group).

Alright, alright, I see what they’re putting down here…

But while I appreciate landmark studies and/or older literature, I figured for time’s sake, let’s move on to something perhaps a little more timely. Besides there being differences in practice when comparing 1993 to today, current Group A Strep may not exhibit the same antibiotic responses as it did back in the day. So I definitely was hoping for something more recent.

Study #2

Cue study #2, or reference #36. This 1999 study published in Pediatrics included 152 children aged 4-18 years presenting with Group A Strep to a single private practice clinic in the US. Patients were assigned 1:1 to amoxicillin 750mg PO once daily or penicillin V 250mg PO TID for 10 days. Outcome measures included the usual clinical and bacteriologic response rates at various time points in therapy. No differences were noted in clinical or bacteriologic responses at 18-24 hours after treatment initiation. As in the last study, amoxicillin demonstrated fewer bacteriologic treatment failures than penicillin V at the later checkpoints (4-6 day and 14-21 day cultures).

Ok, so we’ve got 2 votes in support of a once daily amoxicillin option. Granted, they’re kinda geriatric votes at this point (even the 1999 study is older than many of our readers!), and the second study was single center only. Neither assessed adverse events. Adherence was part of the studies, but it was either a phone call or urine antimicrobial activity assessments, which seems…interesting to try to standardize? I don’t know, maybe there are reference limits for this that I’m not aware of. Regardless, after checking these out, it was time to move on to the last 2 references to see if there was anything a bit more robust…and recent.

Study #3

After perusing the first 2 references, reference #37 felt like hitting the jackpot. This 2006 study in Pediatrics Infectious Diseases seemingly shone like a gem compared to the previous 2. Although still single center, it assigned 652 children aged 3-18 years to either amoxicillin 750/1000mg PO once daily or 350/500mg PO twice daily for 10 days. The dosing options within each arm were available and assigned according to weight <40 kg or >/=40 kg. Outcomes were purely bacteriologic - no clinical response rates, no days lost from school, etc. They went for the hard core culture data only.

What’s refreshing about this study?

It was actually designed as a non-inferiority study, meaning it was intended to prove that once daily was no worse than twice daily when it came to bacteriologic cure rates. The non-inferiority margin was preset at 10%, meaning that the difference in bacteriologic failure rates should not have been more than 10% between the groups in order to be considered non-inferior.

Now, PAUSE. Do you agree that a 10% allowable difference is “no worse?” Would you accept a 90% cure rate instead of a 99% cure rate? I guess it depends on the disease, the individual, the cost, and what the other benefits might be… But I also know myself, and I don’t like settling for less…

Well, let’s take a look at what they found. Bacteriologic failure rates between 14-21 days were 4.53% higher in the once daily group compared to twice daily. Well within the 10% pre specified non-inferiority margin. That being said, the 90% confidence interval had a wiiiide margin of -0.6 to 9.7. Do you think the upper bound of a more rigorous 95% confidence interval would have exceeded the 10% threshold??? Food for thought… I’m willing to bet it may have since, to be more confident that a value falls within the range, the range is wider. At 28-35 days after treatment initiation, bacteriologic failure rates were actually 4.33% lower in the once daily amoxicillin group than in the twice daily cohort (90% confidence interval, -7.7 to -1). Ok, so the response seems durable in the once daily group.

Let’s take a moment for vital information from this study - adverse effects. Medicines only help if patients take and can actually tolerate them! This study did assess GI and other adverse events and found no differences between the once and twice daily regimens. Surprising…but alriiiight.

Phew! Ok, reference #37 here is doing some heavy lifting for presenting once daily amoxicillin as a dosing option for Group A Strep. Not perfect…but what study is?

Study #4

Now on to reference #38, the 4th and final citation noted behind this dosing option. This 2008 study from the Archives of Disease in Childhood feels similar to the last study at first glance. It’s another non-inferiority study, single-center, randomized, etc. The primary outcome was eradication of Group A Strep on throat cultures at 3 different time points during and after a 10 day antibiotic course. Non-inferiority was again defined as a difference of no more than 10% between groups. All seems pretty familiar, eh?

Let’s check out the treatment groups. This study compared amoxicillin 1500mg (or 750mg for weight <30 kg) PO once daily to penicillin V 500mg (or 250mg for weight <20kg) PO twice daily in 353 children. The children included in this study were between 5-12 years old. Assuming the average weight of a 5 year old is ~40 pounds, most of the participants assigned to penicillin likely received the 500mg dose, which makes the twice daily assigned schedule more reasonable.

Had more patients received 250mg doses, twice daily likely wouldn’t have been sufficient, and it could have skewed the interpretation of non-inferiority. Because it certainly could have been easier to demonstrate non-inferiority if you’re not giving the “best of the best dose.” But we’re in luck. It seems not too many participants received just 250mg twice daily based on the dosing weight threshold.

On to the results. At each time check point, the difference in bacteriologic failures was similar between the amoxicillin and penicillin groups. Additionally, the upper bound of the 95% confidence interval for the difference between positive culture rates between the treatment groups remained <10% for all time check points, meeting the prespecified definition of non-inferiority.

Adverse events were not assessed.

And so, the authors again concluded that once daily amoxicillin was non-inferior to the standard penicillin care.

Pharmacokinetic Musings about Once Daily Amoxicillin

I’ll admit, I still don’t fully understand why this works from a kinetic standpoint. The half-life of amoxicillin, while longer than penicillin, is still relatively short at about an hour in adults and 5 hours in neonates. Maybe children are in a sweet spot in between these 2 reported figures such that once a day does the trick?

Beta lactams like amoxicillin are time-dependent in their activity, so you would think that giving a drug with that short of a half-life just once a day wouldn’t be sufficient in staying above the MIC long enough. But perhaps the larger one time dose gives the drug a high enough peak that concentrations stay above the MIC long enough to do the job, even though it’s decaying pretty rapidly. Alternatively, perhaps the answer lies in the half life of the drug at that particular site of action. We know the half life of amoxicillin in middle ear fluid is longer than that reported for serum in adults, so maybe it’s a case of location, location, location?

The tl;dr of High Dose Amoxicillin Once Daily

What do you think? Are these 4 studies enough to convince you that once daily amoxicillin is sufficient (and not any less well tolerated) for treatment of Group A Strep in pediatric patients?

In my opinion, at this point, I was fairly well-convinced. I holstered my barn storming weapons and turned my pharmacokinetic high horse out to pasture. I shared my findings with my pharmacist colleagues, who diffused pretty quickly as well. As pharmacists, we have to be willing to accept surprises when it comes to our knowledge because we can’t know everything!! And we absolutely should continue to investigate and learn new tidbits every day.

Even though this is a post specifically about once daily amoxicillin in pediatric patients, it’s also hopefully a reminder about pharmacy practice. Don’t get stuck in a knowledge rut just because you learned something one way or another, and don’t forget to PAUSE before you go in guns blazing to lay out some drug knowledge. You just might save yourself some embarrassment AND be a better clinician for your patients! Which is really what matters at the end of the day, right?

Long story short, once daily amoxicillin IS acceptable in pediatric patients for the treatment of Group A Strep pharyngitis without any apparent increase in adverse events. Time to fill that script!

A Pediatric Clinical Pearl for Non-Pediatric Pharmacists: Once Daily Amoxicillin