Non-Clinical Topics

Is It Time to Abandon One-Size-Fits-All Dosing for Antibiotics?

by Annette Boyle

October 14, 2018

IOWA CITY, IOWA—Increased obesity among veterans and the general population might be leading to more hospitalizations for infections and greater instance of failed treatment in patients who have been hospitalized.

Researchers at the Iowa City, IA, VA Health Care System recently examined the treatment of cellulitis to better understand high hospitalization and clinical failure rates for the common skin infection. Hospitalizations with cellulitis have increased dramatically in the last few years nationwide and the condition is the third-most-common infectious disease diagnosis at the Iowa City VAMC, according to a recent antimicrobial stewardship study.

In a study published in the Journal of Infection, they determined that inadequate dosing of the most common therapies for cellulitis, clindamycin and trimethoprim/sulfamethoxazole (TMP/SMX), doubled the odds of clinical failure.1

The Infectious Disease Society of America guidelines recommend a range of doses for both drugs, 300-450 mg orally three or four times a day for clindamycin and one or two double strength tablets by mouth twice a day for TMP/SMX but do not provide a basis for determining what dose within those ranges would be appropriate for specific patients or conditions.

Kristin Cox, Author

“Patient size, severity of infection and comorbidities often drive dosing decisions,” explained co-author Kristin Cox, PharmD, MSHE, clinical pharmacist in the inpatient pharmacy at the Iowa City Health Care System. “However, we noticed providers often dose TMP/SMX using a ‘one dose fits all” approach (e.g. 1 double-strength tablet by mouth every 12 hours).’”

Previous studies indicated that patients with cellulitis who had higher body mass index or obesity had worse outcomes in both inpatient and outpatient settings.

The Iowa City team hypothesized that the poor outcomes could be a function of the lipophilic nature of clindamycin and TMP/SMX and that “dose increases may be necessary in the setting of morbid obesity to enhance tissue penetration,” the authors said.

Based on a study by Halilovic and colleagues that indicated that doses below 5 mg/kg per day of TMP/SMX or 10 mg/kg per day of clindamycin were associated with clinical failure, the study team used those cutoffs to analyze the impact of adequate (above the thresholds) or inadequate (below the thresholds) dosing, Cox told U.S. Medicine.2

The multicenter retrospective cohort study evaluated outcomes for 208 patients hospitalized for cellulitis and discharged with a minimum of seven days of antimicrobial therapy with either oral clindamycin or TMP/SMX. The majority of patients (57.7%) received inadequate dosing of clindamycin or TMP/SMX, and inadequate dosing nearly doubled the rate of treatment failure compared to adequate dosing, 30% vs. 17%, respectively. The investigators defined clinical failure as recurrence hospital readmission, emergency department visit or death due to skin or soft tissue infection within 30 days of discharge.

Patients who received an inadequate dose of either antimicrobial had a mean weight of nearly 250 pounds, while those who received an adequate dose had a mean weight of 211 pounds.

Weight and Dosing

To their surprise, the researchers did not find that inadequate dosing was directly associated with weight as a bivariate or continuous variable. “Upon post-hoc analysis we found that providers tended to be more aggressive with dosing among morbidly obese patients compared to overweight or mildly obese patients, in particular with TMP/SMX,” they said.

Still, the results “suggest the IDSA dosing recommendations for clindamycin and TMP/SMX may be inadequate among obese patients,” the authors said.

Inadequate dosing also occurred more often among diabetic patients and those who had an incision and drainage procedure. Patients with elevated CRP values on admission were more likely to receive adequate dosing. “We speculate that providers were more aggressive with antibiotics when CRP values were elevated and less aggressive when source control was presumably achieved,” the authors said.

Brett Heintz, Author

To address the issue, the team “developed a local weight-based dosing table for oral antibiotics often utilized for treatment of cellulitis with the goal of optimizing patient outcomes and reducing complications, including the need for hospitalization,” said co-author Brett Heintz, PharmD, BCPS AQ-ID, AAHIVE, medicine/infectious disease pharmacy specialist at the Iowa City VAMC.

More significantly, the problems identified with standard dosing of these two antibiotics likely apply to many other antimicrobials and might affect the outcomes of a growing proportion of patients, given the increasing number of overweight and obese veterans.

“Lipophilic antimicrobial agents such as doxycycline, linezolid and fluoroquinolones would also be influenced by body stature, thus weight based dosing should be considered when used for the treatment of cellulitis or for any tissue infection,” Heintz told U.S. Medicine.

Other classes of drugs are likely also to fail to reach adequate concentrations in larger patients without adjustment. “Literature also supports that the volume of distribution is also increased for hydrophilic antimicrobial agents (e.g. beta-lactams), albeit to a lesser extent, in the setting of obesity. Further, studies support clearance may be greater in obese compared to non-obese patients among hydrophilic agents, suggesting the need for weight based dosing,” Cox noted.

1. Cox KK, Alexander B, Livorsi DJ, Heintz BH. Clinical outcomes in patients hospitalized with cellulitis treated with oral clindamycin and trimethoprim/sulfamethoxazole: The role of weight-based dosing. J Infect. 2017 Dec;75(6):486-492.

2. Halilovic J, Heintz BH, Brown J. Risk factors for clinical failure in patients hospitalized with cellulitis and cutaneous abscess. J Infect. 2012 Aug;65(2):128-134.

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