Article, Emergency Medicine

Underdosing of common antibiotics for obese patients in the ED

Unlabelled imageAmerican Journal of Emergency Medicine (2012) 30, 1212-1214

Brief Report

Underdosing of common antibiotics for obese patients in the ED?,??

Jada L. Roe MD a, Joseph M. Fuentes MD b, Michael E. Mullins MD b,?

aWashington University School of Medicine, Campus Box 8072, Saint Louis, MO 63110, USA

bDivision of Emergency Medicine, Washington University School of Medicine, Campus Box 8072, Saint Louis, MO 63110, USA

Received 10 March 2011; revised 20 April 2011; accepted 19 May 2011

Abstract

Background: Obesity is a growing problem in the United States. Obesity alters the Pharmacokinetic profiles of various drugs. Although there are guidelines for dose adjustments for many of the antibiotics commonly used in the emergency department (ED), they are seldom used.

Methods: This is an institutional review board-approved retrospective study at an American Society of Metabolic and Bariatric surgery Center of Excellence and a level I trauma center with annual ED volumes of more than 80 000 visits. Data were retrospectively collected from ED pharmacy records during a 3-month period in 2008. Any first dose of cefepime, cefazolin, or ciprofloxacin administered in our ED to a patient recorded as both more than 100 kg and with a body mass index greater than 40 kg/m2 was compared with our hospital guidelines and found to either adhere or not adhere to those guidelines.

Results: There were 1910 orders found to meet the study criteria: 775 orders for cefepime, 625 orders for cefazolin, and 510 orders for ciprofloxacin. Adherence rates for first dose of cefepime, cefazolin, and ciprofloxacin administered, respectively, were 8.0%, 3.0%, and 1.2%.

Conclusion: Emergency physicians frequently underdose cefepime, cefazolin, and ciprofloxacin in obese patients. Underdosing antimicrobials presents risk of treatment failure and may promote Antimicrobial resistance. Education is necessary to improve early antibiotic administration to obese patients.

(C) 2012

Background

The most recent population data show that 1 in 3 adults are obese and that 1 in 20 meet class III or “Morbidly Obese” categorization, defined as a body mass index (BMI) greater

? Source of support: departmental.

?? Prior abstract presentation: American College of Emergency Physicians (ACEP) Research Forum; 6 October 2009; Boston, MA.

* Corresponding author. Tel.: +1 314 747 5585; fax: +1 314 362 0478.

E-mail address: [email protected] (M.E. Mullins).

0735-6757/$ – see front matter (C) 2012 doi:10.1016/j.ajem.2011.05.027

than 40 kg/m2 [1]. Furthermore, the obese population is expanding and predicted to increase to include 700 million people worldwide by 2015.

Attaining therapeutic dosing in these patients is especially important. Obese patients present a greater risk of infection and a higher morbidity and mortality associated with infection than does the general population [2]. Subtherapeu- tic dosing increases the risk of treatment failure, unnecessary escalation to broader-spectrum antibiotics, and selection of resistant pathogens [3].

Optimizing treatment of potentially life-threatening infec- tions in the emergency department (ED) is increasingly

Underdosing of antibiotics for obese patients in the ED 1213

emphasized, with most attention focused on timing as op- posed to adequate dosing.

Methods

This was an institutional review board-approved retro- spective study, initially conceived as a quality improvement review. The study was conducted at an urban, level I trauma center at a hospital with an emergency medicine residency. The hospital is a referral center for obese patients and is recognized as an American Society of Metabolic and Bariatric Surgery Center of Excellence (http://www.asmbs.org).

We retrospectively collected data from pharmacy records to identify each dose of cefepime, cefazolin, or ciprofloxacin administered in the ED to a patient who weighed greater than 100 kg and had a BMI greater than 40 kg/m2 during the study period of January 1 through March 31, 2008. We selected these 3 antimicrobials because of their high volume of use and the availability of guidelines for obese dosing without special weight calculations (such as ideal body weight). Doses could be for any indication. Patients were not ex- cluded based on creatinine clearance or liver function because these parameters would alter only dosage interval and not the first dose. Weights used for the study were the self-reported weights given by the patients at ED triage, which were recorded in the medical record at the time of the ED encounter. Patients in our ED are not routinely weighed. We compared these doses with our hospital guidelines set forth in the Drug dosing and Usage Guidelines (Table 1) created by the Antibiotic utilization Review subcommittee, a specialized team of infectious disease physicians and pharmacists. We classified each dose as either adhering or

not adhering to the guidelines.

These dosing recommendations are based on the available pharmacokinetic, pharmacodynamic, and clinical data [4-6]. The dose recommendations for the included antibiotics are unchanged for several years. Currently, the Infectious Dis- ease Society of America has no guidelines for antimicrobial dosing in obese patients. Our hospital guidelines are included

Table 1 Recommended antibiotic dosing for patients with BMI greater than 40 kg/m2 and body mass more than 100 kg

in a handbook distributed annually to all residents by our pharmacy and are available on the hospital’s intranet.

We decided a priori that 2 doses ordered and given within 4 hours of the initial order would count as one appropriate dose rather than as 2 inappropriate doses.

Results

A total of 1910 orders were placed for patients that met our study criteria for cefepime, cefazolin, or ciprofloxacin during the 3-month study period. Again, only the initial dose, including any additional dose given within 4 hours, was considered. In 3 cases (1 cefepime, 2 cefazolin), the first and second doses were 1 g each and appropriately totaled 2 g. Patient dispositions included admission (69.7%), discharge from ED (29.2%), died in ED (0.5%), transferred to other hospital (0.4%), and left against medical advice (0.1%).

Of the 775 orders for cefepime for obese patients meeting our study criteria in the 3-month period, 62 were appropri- ately dosed for an 8.0% adherence rate. Sixty-one of those 62 were initially ordered correctly as 2 g. One patient had two 1-g doses ordered within minutes of each other.

There were 625 orders for cefazolin, and only 19 were appropriately dosed for patients both weighing more than 100 kg and with a BMI greater than 40 kg/m2, for a 3.0% adherence rate. Seventeen of those 19 were initially ordered correctly as 2 g, and 2 patients received two 1-g doses approximately 1 hour apart.

Of the 510 orders for ciprofloxacin, 6 were appropriately dosed for an adherence rate of 1.2%. No doses were cor- rected within the 4-hour time limit.

Discussion

In general, obesity affects most pharmacokinetic param- eters, except absorption, which appears to be largely unchanged [7]. Volume of distribution (Vd) is typically increased for lipophilic antibiotics (eg, fluoroquinolones) due

Cefazolin

CrCl >=30, 2 g IV, every 8 h

CrCl 10-29 mL/min, 2 g, IV, every 12 h

CrCl b10, 2 g, IV, every 24 h

Cefepime

CrCl >=60

CrCl 30-59 mL/min

CrCl b30

serious infections a

2 g, IV, every 8 h

2 g, IV, every 12 h

2 g, IV, every 24 h

Other infections Ciprofloxacin

IV PO

2 g, IV, every 12 h CrCl >=30

800 mg, IV, every 12 h

750 mg, PO, every 12 h

2 g, IV, every 24 h CrCl b29

800 mg, IV, every 24 h b

750 mg, PO, every 24 h c

2 g, IV, every 24 h

IV indicate intravenous; PO, per os. Sources: References [4-6].

a febrile neutropenia; type 1 ?-lactamase-producing strains; Pseudomonas aeruginosa; cystic fibrosis.

b Or 400 mg, IV, every 12 hours.

c Or 500 mg, PO. every 12 hours.

1214 J.L. Roe et al.

to the increase in adipose tissue, roughly in proportion to the total body water (TBW) [8]. Vd in the obese is also increased for the hydrophilic antibiotics (eg, cephalosporins), roughly in proportion to the lean body weight [8]. This is counterintuitive but understandable because obese patients typically have a higher lean body weight and increased plasma volume and because adipose tissue is 30% water [9]. Clearance (Cl) is more variably affected by obesity. Renal clearance is typically understood to increase due to glomerular hyperfiltra- tion [10,11]. Hepatic clearance can be affected by increases or decreased in phase I or phase II reactions, as well as changes in clearance associated with fatty liver disease, which occurs with an increased prevalence in this population [12].

The efficacy of cephalosporins is time dependent, or proportional to the time kept above the minimum inhibitory concentration (MIC) [13]. Chiba et al [14] and Yost and Derendorf [15] found that both Vd and Cl were increased in obese patients. Edmiston et al [4] then found that patients with bariatric surgery had similar plasma concentrations but significantly lower tissue concentrations after receiving 1-g perioperative doses of cefazolin. Clinical outcome data found that at this 1-g dosing of perioperative cefazolin, the postoperative infection rate was 16.5% in obese patients vs 2.5% for their normal-weight counterparts. When the dose of cefazolin was doubled, infection rate in the obese group dropped to 5.6% [5]. Based on these data, doubling of the usual dose of many cephalosporins is appropriate [13].

Ciprofloxacin efficacy is proportional to the maximum concentration to MIC ratio and the area under the curve to MIC ratio [13]. Data regarding the effects of obesity on Vd and Cl for ciprofloxacin are more conflicting [16]. However, data regarding tissue penetration show the need for higher dosing in obese patients to obtain therapeutic target tissue concentrations [17].

The pharmacokinetic, pharmacodynamic, and clinical data currently available regarding antibiotic dosage adjust- ments in the obese population support the Antibiotic Utili- zation Review guidelines (Table 1) used by our hospital. These guidelines are, however, only adhered to in 8.0%, 3.0%, and 1.2% of first doses administered of cefepime, cefazolin, and ciprofloxacin, respectively. Because early antibiotic administration reduces mortality in life-threatening infections, meeting proper dosing guidelines in the ED should be of the highest priority [18].

A limitation of our study was that compliance with the guideline was used as a proxy for adequate antibiotic con- centrations, which are not commonly available for cefazolin, cefepime, and ciprofloxacin. The study also did not follow the patients to their final outcomes because these doses were given empirically before culture results (if obtained) were available, because the reasons for antimicrobial therapy were varied, and because not all patients completed a full course of the antimicrobial of interest.

Another limitation is the use of self-reported weights instead of measured weights. However, because patients most likely underestimate actual weight, it is highly likely

that patients who reported weights more than 100 kg were indeed more than 100 kg.

Conclusions

Emergency physicians very frequently underdose com- mon antimicrobials in obese patients. Risks of undertreated infections may increase morbidity, length of stay, and anti- biotic resistance. Education on the importance of appropri- ately dosing antibiotics for obese patients is needed.

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