Antibiotic dosing in obese patients can be a major challenge. In this article, an infectious diseases and critical care pharmacist with significant experience in this area is interviewed and insights on the topic are provided.
Interview with: Lina Meng, Pharm.D., BCPS, BCCP
Interview By: Timothy P. Gauthier, Pharm.D., BCPS-AQ ID
[Last updated: 28 December 2017]
Selecting an antibiotic dose can be a challenging task, because it requires consideration for complex patient-specific pharmacokinetic (PK) and pharmacodynamic (PD) factors. Things such as drug absorption, drug concentration at the site of infection, and microbial resistance are just a few of the many variables to account for.
When approaching antibiotic dosing in special patient populations (e.g., pediatrics, obesity, critical illness), the challenge of selecting a reasonable dose becomes even more difficult, as literature in these areas tends to be limited.
Focusing on antibiotic dosing in obesity, this is an important issue in the United States today. Obesity rates in the American population have been trending upwards since before the year 2000. The Centers for Disease Control and Prevention (CDC) provide data from 2015-2016 on this topic, which show the rate of obesity in American youth is 18.5% and a staggering 39.6% in American adults. In this instance obesity in youth is defined as a body mass index (BMI) > the age- and sex-specific 95th percentile of CDC growth charts published in 2000 and in adults is a BMI > 30.
As pharmacists, physicians, and others continue to grapple with the challenges of antibiotic dosing in obese patients it can be helpful to acquire new resources and insights. Recently, Dr. Lina Meng and colleagues published a comprehensive paper on this topic:
I reached out to Dr. Meng for an interview and she graciously accepted the invitation. In an effort to promote discussion and share new updates from the literature, the following insights on antibiotic dosing in obesity are provided.
1. What motivated you to write a review about antibiotic dosing in obese patients?
From a practice standpoint we had been getting more antibiotic dosing questions about obese patients, especially with newer agents such as linezolid, daptomycin, and ceftolozane-tazobactam. In addition, our institute’s implementation of extended infusion piperacillin-tazobactam, cefepime, and meropenem prompted us to examine dosing requirements for our workhorse antibiotics.
During our literature review of antibiotic dosing we realized that a surprisingly large body of data had been published in the last 10 years since the 2007 article by Pai et al., which described antimicrobial dosing considerations for obese adult patients. In turn, it seemed a good time to provide an update on antibiotic dosing in this special population.
We had initially envisioned creating a practical clinical guide for dosing antibiotics in obese patients. Within this guide we were considering to include a subsection on dosing antibiotics in obese patients with critical illness. The guide would review alternative dosing strategies (e.g. continuous or prolonged infusions), guidance on appropriate body-weight for weight-based dosing, considerations for certain pathogens and resistance patterns, factors that come into play with continuous renal replacement therapy (CRRT), and more. As the project developed we eventually decided to pursue the comprehensive guidance paper we published in Pharmacotherapy.
2. Are there one or two things that you learned during the project that really surprised you?
Yes.
First, I found the differences that exist within antibiotic classes to be striking. One example is seen with the carbapenems, for which the volume of distribution (Vd) is generally increased in obese patients. However, while meropenem requires dose adjustment in critically ill obese patients with a creatinine clearance (CrCl) > 100 mL/min, doripenem and ertapenem do not.
The findings within the cephalosporins are also largely variable. Ceftaroline, ceftolozane-tazobactam, and ceftazidime-avibactam do not appear to require dose modifications in obesity, while cefepime and ceftazidime may.
Second, heterogeneity in study designs was surprisingly common in the published literature. Not only in the number and types of studies, but also the frequently conflicting PK changes reported for evaluations of the same antibiotic. This likely stemmed from heterogenous patient populations studied.
Obese patients frequently have concomitant comorbidities or illnesses (e.g., augmented renal clearance, sepsis, hypoalbuminemia, critically ill on dialysis) that complicate dosing in obesity. We attempted to address concomitant factors in our dosing guidance whenever possible. For example, in critically ill septic patients >90 kg on CRRT with pathogens demonstrating minimum inhibitory concentrations (MICs) > 0.5 mg/L, we recommend ciprofloxacin doses up to 400mg IV every 8 hours.
In some cases, we could not give firm recommendations due to insufficient evidence, as is the case with nafcillin, for which a single case study reported a near doubling of the Vd in an obese patient and concluded that higher doses are needed in obesity.
3. If you had to pick two “most important themes” about antibiotic dosing in obese patients, what would they be?
FIRST: Increases in PK parameters in obesity (especially Vd) may not lead to the need for clinically relevant dosing modifications. One should assess relative changes in Vd and clearance (CL), since each can be altered to different extents in obesity.
Relative changes in the ratio of Vd and CL (related by k= CL/Vd) alter elimination half-life, which ultimately impacts maintenance doses. There are cases where the extent of PK changes in obesity may not be large enough to hinder PD achievement at typical MIC values. For example, ceftolozane’s increased Vd and minimal increases in CL did not result in clinically relevant changes in exposure.
Extremely low or high CrCl can outweigh changes in Vd and become a significant driver of dosing requirements of antimicrobials that are renally eliminated. Higher CrCl was a risk factor for failure for several beta-lactams. Our dosing recommendations for piperacillin-tazobactam, cefazolin, meropenem, levofloxacin, and vancomycin incorporate dosing considerations in those with increased CrCl (i.e., use of extended infusions, higher doses, more frequent dosing, and/or more intensive TDM).
SECOND: Dosing in obese patients should still incorporate general dosing principles and considerations: the site of infection, pathogen MIC, and PK/PD target. For example, in urinary tract infections, the dosing of antibiotics that achieve high urinary levels are probably similar in obese and non-obese patients.
4. Based on your research are there any scenarios that come to mind in which you would try to avoid using a particular antibiotic due to a patient being obese?
Higher colistin or polymyxin B doses that may be seen in obese patients may unfortunately put the patient at unacceptably high risks of nephrotoxicity. Dose capping at proposed maximum doses (360 mg and 200mg daily, respectively) may lead to inadequate PK/PD achievement at higher MICs, which may be seen in infections with Psueomonas aeruginosa and Acinetobacter baumannii. In such instances, alternative agents should be considered.
5. Clearly there is still a lot to learn about antibiotic dosing in obese patients, but where do you see the greatest need for more research on this topic?
The data available is still largely limited to case reports, case series, and scattered PK/PD studies- much of the PK findings are conflicting (see study details in the supplement that accompanied our paper).
There is also a lot unknown about the effects of different degrees of obesity (particularly in those with BMI > 40) and PK/PD in deep-seated infections or those involving intracellular pathogens. Therapeutic drug monitoring is increasingly important in this population.
Ultimately, we need to know if dosing modifications correlate with improved clinical outcomes.
6. Do you have any recommended additional readings or resources you would direct people to for learning more about antibiotic dosing in obese patients?
In addition to our recent article in Pharmacotherapy, a classic article from the Society of Infectious Diseases Pharmacists authored by Dr. Pai and Dr. Bearden is:
An additional article readers may find helpful is from Dr. Payne et al. on dosing antifungal agents in obese patients:
About the interviewee
Lina Meng graduated from University of California-Berkeley with a BS in molecular and cell biology (2005) and from University of California-San Diego School of Pharmacy (2009). She completed her PGY1 Pharmacy Practice Residency at the University of California-San Francisco, and her PGY2 Critical Care Residency at Stanford.
Dr. Meng joined the Stanford Antimicrobial Safety and Sustainability (SASS) Program in 2015. She provides clinical service to the Infectious Diseases (ID) Consult Services, and precepts pharmacy residents on the ID rotation and ID fellows on the antimicrobial stewardship rotation. Learn more about the Stanford SASS team here and follow or connect on Twitter @StanfordASP.
I would like to express my sincerest appreciation to Dr. Meng for taking the time to complete this interview and share here perspective about this important healthcare topic.
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