Monday, August 30, 2010

Antibiotic Underdosing in "Obesity"

One of the most critical areas of research in improving treatment and outcomes for "obese" people is the issue of weight-based dosing. 

In many drugs, dosages have been determined based on the norm of average-sized people.  This means that people who are significantly under or over this "norm" may not be receiving the dosage most optimal for their size, with lean folk potentially being overtreated and fat folk likely being vastly undertreated. 

Underdosing is of particular concern for "obese" people because it may lead to subtherapeutic concentrations of drugs and deteriorating outcomes over time.

However, deciding on optimal drug dosages is not a simple task.  Concern for obtaining the most effective dose must be balanced against concern over toxicity from a too-large dose. 

In the past, doctors were understandably reluctant to prescribe a very large dose of various medications for people with larger bodyweights because they were concerned about the potential for massive toxicity. 

In fact, doctors sometimes intentionally reduced the dose because they were concerned about greater possible toxicity in "obese" people.

Now, however, there is emerging evidence that in many drugs, outcomes are improved with the larger doses and suboptimal with smaller doses. 

This is one of the most pressing issues in pharmocotherapy because extensive research is needed to determine optimal dosing and which drugs benefit most from weight-based dosing, but this research has been slow to happen.  And even when the research is there, some doctors have been slow to adopt new guidelines. 

Let's look at several critical areas in which underdosing is a major issue.  First up.....antibiotics.

Antibiotic Underdosing

Antibiotic underdosing in "obese" people may be one reason why fat people have poorer outcomes after surgery and/or infections.  Furthermore, underdosing may be a particularly serious problem in very fat people. 

Remember, when you are on antibiotics, you are cautioned to take the entire prescription, not to stop when you start feeling well.  If you stop too soon, the bug may still be there at low levels. Then, when the antibiotics are stopped, the bug may opportunistically spring back to life in a more severe or antibiotic-resistant form. 

A similar effect may happen when "obese" people are underdosed with antibiotics.  The bug may be only partially knocked out, return in time stronger than before, or worse, develop a resistance to the subtherapeutic-level antibiotic.

This may be one reason (among several) why infection is a particular problem for "obese" people after surgery....the antibiotic dosages given to them may not be strong enough

Of course, different drugs work by different mechanisms.  Therefore, not all drugs need weight-based dosing because of the unique way they work........but it's clear that some do, and that the importance of this factor is only now becoming more recognized in the medical field. 

For example, even recent research (see study abstracts below) shows that:
  • Many "obese" people are still routinely underdosed with antibiotics, especially "morbidly" and "super-obese" people
  • Revised guidelines for weight-based dosing are underutilized by healthcare professionals
  • Far more research needs to be done into the most effective drug dosages for people of varying sizes, but particularly for very fat people
It's very disappointing that there isn't more definitive information on this topic in this day and age.  You would think that this would have been well-studied by now.....or that there would be a tremendous push for more research on this right now, given recent studies showing the problem. 

Yet there really doesn't seem to be a sense of urgency or priority on this in the research.  There are a number of studies noting the paucity of research on the topic and pointing out the need for more, but there are few studies actually conducting research into this important area. 

[Ironically, what studies there are often are on weight-loss surgery patients. We may finally be starting to get data on drug dosages for very fat people, if only because bariatric surgeons need to improve their surgery stats.]

At the very least, more doctors should be aware of what research and guidelines we do have for more effective dosing...but they apparently aren't because it doesn't seem to be affecting the way many of them prescribe (see vancomycin study below).

You have to wonder how many fat people have died or been gravely ill because their doctors didn't utilize the most effective dosage for them.

This is really a critical area for future research and education among health-care professionals. But until they start paying more attention to this issue, it's up to us, as fat consumers, to push for more action and to advocate strongly for ourselves if we get sick. 

Standardized Dosing

Another problem that commonly leads to chronic underdosing of "obese" people is standardized dosing, where little or no flexibility is offered to the doctors regarding dose size. 

Weight-based dosing is all well and good when it's easy to adjust dosages (as in IV antibiotic therapy in the hospital) but many commonly-prescribed antibiotics are only offered in a "one-size-fits-all" package.

For example, a few years ago, I developed a roaring secondary bacterial infection around a holiday and went to an emergent care center to get quick treatment for it.  They recognized I really needed antibiotics at that point.  I asked them about weight-based dosing, and the doctor admitted that weight-based dosing probably would be more beneficial for someone of my size.  However, he pointed out that he had no choice because the medication only came in one dosage.  It was that or nothing. 

I needed two rounds of antibiotics to beat that bug.  The first one started to knock it out, and then it came back a couple of weeks later, stronger than ever (at which point I started coughing up blood). I'm lucky the bug got wiped out by the second dose of antibiotics. If I had been older or more fragile, that bug might easily have gotten me because it was a really nasty one.

Was my delayed recovery because I was underdosed due to standardized dosing?  Hard to know for sure because I've not found a lot of dosing information about that particular antibiotic, but I suspect underdosing might well have played a role. And how even more undertreated might I have been had I been truly supersized?

Of course, sometimes standardized dosing is logical.  In an emergency, no one has time to stop and figure out weight-based dosing and dispense it.  In situations where time is of the essence (i.e. trauma surgery, emergent cesareans), having standardized doses available makes sense. 

But many surgeries are pre-planned and there is plenty of time to figure out the proper dosage of antibiotic to really lower the chances of wound infection.  Yet, hospital protocol or lack of knowledge/data about weight-based dosing often prevents its use even when time allows for it. 

So although I'm still learning about this topic (and welcome feedback from healthcare professionals who are well-versed in pharmocotherapy), I think it's important to:
  • Start raising awareness among fat people to ask more questions from their healthcare providers about weight-based dosing and when it's needed
  • Ask healthcare professionals to raise their awareness of the issue
  • Start pressuring healthcare researchers to do further study of this important topic
If half of Americans are "overweight" or "obese," then prompt attention to this issue is quite pressing so that outcomes can be improved in this group.

This problem is also pressing to the general public because antibiotic resistance is on the rise. If subtherapeutic levels lead to more antibiotic resistance, then underdosing "obese" people may be adding to the critical public health issue of antibiotic resistance.

Therefore, finding out and promoting the proper dosages for people of size may benefit not only fat people, but society as a whole. 

Research on Antibiotic Underdosing

In the meantime, here are two recent study abstracts on the topic of antibiotic underdosing in "obese" people. I was particularly struck by the vancomycin study. 

Vancomycin is a very strong antibiotic, typically used for severe infections; in the past it was often a drug of last resort.  Therefore, proper dosing of it is critical, especially the initial dose to "knock out" the infection, and then therapeutic dosages to keep the infection down and out afterwards.

Yet in the study, only 1/3 of "obese" patients received an "adequate" initial dose of vancomycin.

If you look at the full text of the study (available here), you see that when they further examined dosage by class of obesity, NONE of the people with BMI greater than 40 received an adequate initial dosage.

Furthermore, less than 1% of the whole "obese" group received the recommended weight-based dose.

They concluded: 
Our results highlight the fact that obese patients may be routinely underdosed as a result of the widespread practice of prescribing fixed-dose vancomycin.
The authors also noted that another study has suggested that dosing intervals may need to be more frequent in the "obese" population in order to maintain minimum therapeutic levels, which is another intriguing consideration. 

Other studies have found that it's not only the dosage of antibiotics that counts, it's also the length of treatment.  "Morbidly obese" people may benefit from a longer course of antibiotics than is standard.

Furthermore, recent studies have found that in particularly infection-prone areas, application of additional topical antibiotics into the surgical incision area significantly reduces the rate of post-operative infection. 

So the the concept of antibiotic underdosing may not just be about how much antibiotics should be given to fat people, but also where they are given, how often they should be given, and for how long. 

I'd love to see more specific studies devoted to these questions.

Final Thoughts

If antibiotic underdosing is so common in people of size, is it any wonder that "obese" patients have poorer outcomes from infections and after surgery? 

Granted, many variables factor into why "obese" people respond less effectively to wounds and infections, and antibiotic underdosing is definitely not the only issue.  It's important to be fair about that.  It's not only about antibiotic dosing.

However, underdosing is quite likely a vastly underestimated reason for poorer outcomes, and one that should be relatively easy to fix, given more awareness of and research into the problem.  We can't do a lot about other factors that cause poorer outcomes and higher infection rates, but dosing is a relatively easy problem to fix.

Therefore, it seems extremely important to me to raise more awareness around this issue and start pressing for more and better research on the topic.

Here are the research abstracts.  (Obviously, highlights and emphasis are mine.)

Multicenter evaluation of vancomycin dosing: emphasis on obesity. Hall RG 2nd, Payne KD, Bain AM, Rahman AP, Nguyen ST, Eaton SA, Busti AJ, Vu SL, Bedimo R.  Am J Med. 2008 Jun;121(6):515-8.

Department of Pharmacy Practice, Texas Tech University Health Sciences Center, School of Pharmacy, Dallas, Texas, USA.

BACKGROUND: There is a paucity of data available regarding the dosing of antimicrobials in obesity. However, data are available demonstrating that vancomycin should be dosed on the basis of actual body weight.

METHODS: This study was conducted at 2 tertiary care medical centers that did not have pharmacy-guided vancomycin dosing programs or other institutional vancomycin dosing policies or protocols. Patients who received vancomycin between July 1, 2003, and June 30, 2006, were stratified by body mass index and randomly selected from the computer-generated queries. Patients greater or equal to 18 years of age with a creatinine clearance of at least 60 mL/min who received vancomycin for at least 36 hours were included.

RESULTS: Data were collected on a random sampling of 421 patients, stratified by body mass index, who met the inclusion criteria. Most patients in each body mass index category received a fixed dose of vancomycin 2 g daily divided into 2 doses (underweight 82%, normal weight 90%, overweight 86%, and obese 91%).

Adequate initial dosing (greater than or=10 mg/kg/dose) was achieved for 100% of underweight, 99% of normal weight, 93.9% of overweight, and 27.7% of obese patients (P less than .0001).

Ninety-seven percent of underweight, 46% of normal weight, 1% of overweight, and 0.6% of obese patients received greater than or =15 mg/kg/dose recommended by several Infectious Diseases Society of America guidelines.

Pharmacists also failed to correct inadequate dosing because only 3.3% of patients receiving less than 10 mg/kg/dose had their regimen changed in the first 24 hours of therapy.

CONCLUSION: In this multicenter pilot study, obese patients routinely received inadequate empiric vancomycin using a lenient assessment of dosing. Greater efforts should be undertaken to ensure patients receive weight-based dosing because inadequate dosing can lead to subtherapeutic concentrations and potentially worse clinical outcomes.

PMID: 18501233   Full text available here

Antimicrobial dosing considerations in obese adult patients. Pai MP, Bearden DT.  Pharmacotherapy. 2007 Aug;27(8):1081-91.

Division of Pharmacy Practice, College of Pharmacy, University of New Mexico, Albuquerque, New Mexico, USA.

As obesity continues to increase in prevalence throughout the world, it becomes important to explore the effects that obesity has on antimicrobial disposition. Physiologic changes in obesity can alter both the volume of distribution and clearance of many commonly used antimicrobials. These changes often present challenges such as estimation of creatinine clearance to predict drug clearance.

Although these physiologic changes are increasingly being characterized, few studies assessing alterations in tissue drug distribution and the effects of obesity on antimicrobial pharmacokinetics have been published. The available data are most plentiful for antibiotics that historically have included clinical therapeutic drug monitoring.

These data suggest that dosing of vancomycin and aminoglycosides be based on total body weight and adjusted body weight, respectively. Obese patients may require larger doses of beta-lactams to achieve similar concentrations as those of patients who are not obese. Fluoroquinolone pharmacokinetics are variably altered by obesity, which prevents a uniform approach. Data on the pharmacokinetics of drugs that have activity against gram-positive organisms-quinupristin-dalfopristin, linezolid, and daptomycin-reveal that they are altered in the presence of obesity, but more data are needed to solidify dosing recommendations. Limited data are available on nonantibacterials.

An understanding of the physiologic changes in obesity and the available literature on specific antibiotics is valuable in providing a framework for rational selection of dosages in this increasingly common population of obese patients.

PMID: 17655508


Anonymous said...

wow thanks for this...enlightening and well writeen...bravo! i wonder how many of us fatties die every year with complications from dosing, and how tht would effect the OMG fat will kill you stats the CDC likes to throw around (even though they were forced to change their numbers by a whole decimal point...but no one seems to have digested THAT information)

Paul Ernsberger said...

Nice essay! The primary consideration is whether the drug is lipophilic or lipophobic (in the chemical sense, not the psychological sense!). Most antibiotics are hydrophilic (or lipophobic) and do not take residence in fat deposits. Vancomycin is an exception, and it is often given in critical situations such as cellulitis. I know many supersized people who have died of cellulitis, and I wonder how many times underdosing of lipophilic antibioltics may have contributed to their deaths.

Figure8onaDate said...

Thank you so much for writing about this. I was totally unaware of this crucial issue that could profoundly impact my health care. I will be discussing this with my doctors the next time I get ill and I hope that the research in this area continues and is utilized by doctors in the field sooner than the usual 15 year window it takes for research recommendations to be implemented in practice.

Sara A. said...

We also need to have weight based dosing in hormonal birth control. It's like an evil algebra problem. If I am 250 lbs and the medication's dosing is proven effective up to 230 lbs, and hormonal birth control is my only method of pregnancy prevention, then how long is it before I become pregnant?

Hazelnut said...

"One-size" dosing is a poor excuse to decline weight-based dosing -- surely it could be handled by a compounding pharmacy.

Anonymous said...

I can't say I'm surprised. Researchers have made barely any effort to figure out how drugs affect women differently, and women are more numerous than "obese" people.