See Article, p 199
Please Sir, I want some more?
—Charles Dickens, Oliver Twist (1839)
Perhaps there are no words more famous from the historic novel by Charles Dickens, Oliver Twist.1 This piece of prose describes a famished young Oliver asking for a second bowl of his allotted thin gruel.
While poor Oliver Twist is remembered for asking for more, when it comes to drug administration in obese subjects, anesthetic pharmacologists have been asking for less.
We have been working to debunk the myth that obese patients need more drug amounts because of their increased size. This research has focused mainly on induction agents and, to a lesser extent, opioids. In these studies, a central theme has prevailed: less is more.2 When dosing scalars (eg, total body weight) have been used, an overdose of anesthetic is much more likely. Doses should be tapered and based on smaller dosing scalars, such as lean body weight.2
In this issue of Anesthesia & Analgesia, Eley et al3 have published an intriguing article examining the effects of obesity on antibiotics. The study population—the obese parturient—is not only prevalent but at a much higher risk for surgical-site infections.4 The authors performed a pharmacokinetic analysis of cefazolin in bariatric parturients, using both plasma samples as well as interstitial fluid samples as a measure of the tissue effect site. This study is long overdue as obese patients in general have physiologic changes that alter the pharmacokinetics of antibiotics. These include changes in body composition, cardiac output, and regional blood flow anomalies—all of which affect drug distribution. Despite increases in cardiac output, blood flow to the adipose tissue decreases with increasing obesity.5 This, in turn, may affect tissue uptake of antibiotics and, therefore, reduce therapeutic effect. An increase in cardiac output is also seen during pregnancy. In addition, other physiologic changes that occur during pregnancy (eg, increases in total body water, adipose tissue, and renal blood flow and a decrease in plasma albumin concentration) may also affect the disposition of drugs, including antibiotics.6
The therapeutic efficacy of cefazolin and β-lactams, in general, require that the concentration of drug in the tissue of interest remain above the minimum inhibitory concentration (MIC) of the bacteria of interest for a certain period of time (Figure). This is known as the time above MIC. Therefore, the dose of cefazolin must be high enough to not only achieve a concentration above the MIC but also maintain this concentration for 40%–50% of the dosing interval to produce adequate clinical and microbiological efficacy.7 The Figure illustrates that even when plasma concentrations are maintained above the MIC for 4 hours, the time above MIC for interstitial fluid is much shorter.
The majority of the published clinical and pharmacokinetic evidence guiding antibiotic dosing in obese subjects is comprised of retrospective data or small prospective studies with a great deal of heterogeneity.8 Numerous pharmacokinetic studies have found that a 2 g bolus of cefazolin was insufficient to obtain plasma or tissue drug concentrations above MICs in obese subjects.9,10 These studies suggested a higher dose of 3 g for these patients. On the other hand, other studies have found that a 2 g bolus did indeed result in adequate antimicrobial prophylaxis.11,12 Despite these conflicting reports, in 2013, collective guidelines were established that recommended a dose of 3 g for subjects weighing >120 kg.13
Eley et al3 measured plasma cefazolin concentrations and also used microdialysis to measure interstitial fluid antibiotic concentrations. This can be considered the greatest strength of this study. Obese patients have reduced antibiotic tissue penetration.14 In fact, there is an inverse relationship between body mass index and cefazolin tissue concentrations.14 Looking only at plasma antibiotic concentration gives only a limited quantification of effective dose. Unfortunately, until only recently, plasma concentrations have historically driven antibiotic dosing recommendations.15
The reduced tissue blood flow seen in obese subjects results in less peripheral drug distribution. With reduced tissue uptake, an increased amount of intravenously administered drug will remain in the central pool. The implications of reduced peripheral distribution, when administering intravenous induction agents and opioids to obese subjects, means more drug is available for the effect site of these agents—the central nervous system. However, when the peripheral tissue serves as the effect site, as is the case of antibiotics, therapeutic concentrations may not be reached since these tissues receive less blood flow. It stands to reason that given the limited blood flow to adipose and subcuticular tissue, a higher plasma concentration is therefore necessary to maintain a suitable concentration gradient to support diffusion of drug into the site of action.
We can commend Eley et al3 for providing simulations of various dosing regimens demonstrating how different doses and dose intervals affect plasma and interstitial fluid concentration over time. Not only does this study demonstrate that our current practice may be inadequate to achieve optimal antibiotic concentrations in obese pregnant women but provides 2 separate regimens that achieve target attainment, thus, guiding the clinician and possibly laying the foundation for a change in antibiotic prophylaxis.
The authors qualify their findings, stating that prospective validation demonstrating a reduction in surgical-site infections is ultimately necessary to change clinical practice. We can agree with this. This study certainly warrants further prospective validation. A prospective study using a larger sample size and outcomes analysis is necessary to determine if these new dosing recommendations impact the incidence of surgical wound infections after cesarean delivery. Until then, the results of this study by Eley et al3 are suggestive but do not confirm that a change in practice is necessary. This study however should cause clinicians to question their current practice—are we administering an appropriate amount of antibiotics to adequately achieve antimicrobial prophylaxis in obese patients? The pharmacokinetic data presented by Eley et al3 strongly suggest that obese pregnant patients are being under-dosed. Therefore, when administering antibiotics to obese parturients, we should be compelled to follow Oliver Twist and ask: may we have some more?
Name: Jerry Ingrande, MD, MS.
Contribution: This author wrote this manuscript.
This manuscript was handled by: Ken B. Johnson, MD.
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