impact of hospital guideline for weight-based antimicrobial dosing in morbidly obese adults and...

7/26/2019 Impact of Hospital Guideline for Weight-based Antimicrobial Dosing in Morbidly Obese Adults and Comprehensive L

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Review Article

Impact of hospital guideline for weight-based antimicrobial dosing in morbidly

obese adults and comprehensive literature review

A. K. PolsoPharmD, J. L. LassiterPharmD and J. L. Nagel PharmD

Department of Pharmacy, University of Michigan Hospitals and Health Centers, Ann Arbor, MI, USA

Received 31 March 2014, Accepted 7 August 2014

Keywords:antibiotics, antimicrobials, obesity, pharmacodynamic, pharmacokinetic

SUMMARY

What is known and objective: Obesity is a signicant burden onthe healthcare system in the United States, and determining the

appropriate antimicrobial dosing regimen in morbidly obesepatients is challenging. Morbidly obese patients have docu-

mented differences in pharmacokinetic and pharmacodynamic

properties compared to normal-weight patients, which impact

antibiotic efcacy and toxicity. The Food and Drug Administra-

tion does not recognize obesity as a special population and does

not require pharmaceutical companies to perform studies spe-

cic to obese patients. However, there are an increasing number

of post-approval studies in obese patients, and this manuscript

reviews available clinical and pharmacokinetic literature regard-

ing weight-based antimicrobial agents. Additionally, we

describe a single-centre approach to optimize dosing in mor-

bidly obese patients.

Methods:A comprehensive literature search was performed on15 weight-based antimicrobials in the setting of obesity: acyclo-

vir, aminoglycosides, amphotericin B, cidofovir, colistimethate,daptomycin, ucytosine, foscarnet, ganciclovir, quinupristin/

dalfopristin, trimethoprim/sulfamethoxazole, vancomycin and

voriconazole. A weight-based antimicrobial dosing guideline for

morbidly obese patients was developed. An analysis of guide-

line compliance and cost analysis were performed following

guideline implementation.

Results and discussion: This review describes the pharmacoki-netic changes that occur in obese patients, including increased

volume of distribution, altered hepatic metabolism, renal excre-

tion and changes in protein binding. The majority of weight-

based antimicrobials result in increased serum concentrations in

morbidly obese patients compared to normal-weight patients

when the calculated dose is based on actual body weight.

What is new and conclusion: This review demonstrates different

antibiotic pharmacokinetic properties are altered in obesepatients that could impact efcacy and toxicity. A single-centre

guideline for weight-based antimicrobial dosing in obesity was

developed and provides recommendations for using ideal body

weight, adjusted body weight or actual body weight when

calculating antimicrobial doses. However, more research is

needed to better elucidate optimal dosing of weight-based

antimicrobials in obesity, with particular focus on efcacy and

toxicity.

WHAT IS KNOWN AND OBJECTIVE

Obesity is a major issue in the United States, with 78 million USadults and 125 million children and adolescents classied asobese [body mass index (BMI) greater than or equal to 30].1 Thisequates to an obesity rate of 35% and 169% in adults and childrenin the United States, respectively.1 Physiological changes in obesitycan alter immunological pathways and increase the risk of centralline infection, post-operative surgical site infections, intensive careunit length of stay and risk for severe pneumonia and inuenza.25

Additionally, changes in antimicrobial pharmacokinetic andpharmacodynamic properties are well documented, which impactclinical success and risk of toxicity.25 Despite the unique charac-teristics of the obese patient population, the Food and DrugAdministration does not require pharmaceutical manufacturers toevaluate dosing recommendations in obesity. Calculating a

weight-based antibiotic regimen is particularly concerning, asmost antimicrobials do not signicantly penetrate adipose tissuewhich results in increased serum concentrations in morbidly obesepatients.25 Some studies recommend using ideal body weight(IBW) or adjusted body weight (AdjBW) when calculating anantimicrobial dose in morbidly obese patients to strike a balancebetween obtaining adequate serum antibiotic concentration toeffectively treat an infection while attempting to minimizepotential toxicities (Table 1).26 Weight-based antimicrobials inthis review include acyclovir, aminoglycosides, amphotericin B,cidofovir, colistimethate, daptomycin,ucytosine, foscarnet, ganci-clovir, quinupristin/dalfopristin, trimethoprim/sulfamethoxazole,vancomycin and voriconazole. General dosing recommendationsin obesity are provided for each agent reviewed; however, theclinician must balance toxicity with efcacy on a case-by-case basis

to avoid treatment failure and promotion of antimicrobial resis-tance. Evaluation of compliance rates and cost savings areanalysed following implementation of weight-based antimicrobialdosing recommendations in morbidly obese patients at theUniversity of Michigan Hospitals and Health System (UMHS).

PHARMACOKINETIC ALTERATIONS IN OBESITY

Differences in proportion of adipose tissue, lean muscle tissue anduid status can greatly affect pharmacokinetic differences betweenpatients, and absorption, distribution, metabolism and excretionare altered in obese patients (Table 2). Modest changes in oral

Correspondence: J. L. Nagel, Department of Pharmacy, University ofMichigan Hospitals and Health System, 1111 E. Catherine Street, Room300, Ann Arbor, MI 48109, USA. Tel.: +1 734 936 2264; fax:+1 734 615 2314; e-mail: [email protected]

2014 John Wiley & Sons Ltd 1

Journal of Clinical Pharmacy and Therapeutics, 2014 doi: 10.1111/jcpt.12200


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absorption can occur in obesity secondary to delays in gastricemptying, likely caused by differences in dietary habits comparedto non-obese subjects.6 Drug absorption is also delayed orincomplete following subcutaneous injections in morbid obesity.Intramuscular injections may also inadvertently be given as a deepsubcutaneous injection due to increased quantity of adiposetissue.6

The volume of distribution (Vd) in obesity can be dramaticallydifferent compared to normal-weight patients.2,4,5 The extent ofchange of drug distribution is primarily based on its intrinsiccharacteristics such as molecular size, degree of ionization, extent

of lipid solubility, protein binding and ability to cross biologicalmembranes.7 Obesity does not signicantly alter albumin bindingof medications but may have alterations in lipoproteins andalpha1-acid glycoprotein although studies are inconclusive.8,9

Other physiological changes, such as tissue blood ow and

changes in cardiac output, can also alter drug distribution,although the signicance of these changes is yet to be deter-mined.6,7

Physiological changes in the liver and kidneys of obese patientscan alter metabolism and excretion.2,4 The increased presence offatty inltration in the liver can alter blood ow and thus drugmetabolism.6,7 Additionally, level of cytochrome P450 pathwayactivity might be altered in obese patients. One study demon-strated increased activity of CYP2E1 and reduced CYP3A4 inobesity, with trends towards change with other CYP isozymes.9

Obesity can increase glomerular ltration rate (GFR), but thisobservation is primarily associated with otherwise healthypatients.2 Obesity in the presence of other comorbidities, especiallyhypertension, can increase the risk for chronic renal dysfunction.2

A study conducted in healthy obese patients utilizing common

equations for evaluating creatinine clearance or estimated GFRshowed both overestimation and underestimation when comparedto measured GFR, which can impact the dose and frequency ofantimicrobials.10 Similarly, obese patients in intensive care unitsmay have larger uctuations in beta-lactam serum concentra-tions.11

REVIEW OF ANTIMICROBIAL AGENTS

Aminoglycosides

Pharmacokinetics of amikacin, gentamicin and tobramycin inobesity are well documented and described in at least 11 humanstudies (Table 3). Most studies demonstrate a need for doseadjustments in obesity and recommend use of AdjBW. The

recommended correction factor varied slightly among studies,which is likely the result of different patient populations anddosing regimens.2,1221 Nine studies recommend AdjBW withadjustments ranging from 020 to 058 [IBW plus 2058% differencebetween actual body weight (ABW) and IBW].2,12,13,1518,20,21 Onlyone study did not nd a difference in pharmacokinetics betweenobese and normal-weight patients.19 This study examined genta-micin and tobramycin in 27 obese peri-partum women and wasunderpowered to demonstrate statistical signicance.

The available literature evaluating aminoglycoside dosing inobesity often has small sample sizes, includes single-dose phar-macokinetic studies and rarely assesses safety. However, theresults largely support the use of AdjBW when dosing aminogly-cosides in obesity, often with a weight of IBW plus approximately40% of the excess body weight. Additionally, obesity recommen-

dations are provided in the tobramycin prescribing information,which recommends use of AdjBW [lean body weight (LBW) plus40% of the excess body weight] when calculating a dosingregimen.22

Colistimethate

Colistimethate studies in obesity are described in three retrospec-tive studies, one prospective study and one case report.2327 Aprospective study by Garonziket al.26 examined pharmacokineticsof colistimethate in approximately 100 patients with doses rangingfrom 75 to 410 mg daily. A linear pharmacokinetic model was

Table 1. Equations used to calculate body mass index (BMI), leanbody weight (LBW), ideal body weight (IBW) and adjusted bodyweight (AdjBW)

Measure Formula

BMI (kg/m2) BMI = ABW/(height in metres)2

IBW kg) Males: IBW = 50 + 23 (height in inches 60 inches)Females: IBW = 455 + 23 (height in inches 60 inches)

LBW (kg) Males: LBW = [9270 9 ABW]/[6680 + (216 9 BMI)]

Females: LBW = [9270 9 ABW]/[8780 + (244 9 BMI)]AdjBW (kg) AdjBW = IBW +[(ABW IBW) 9 correction factor]

ABW, actual body weight.

Table 2. Physiological and pharmacokinetic factors altered inobese patients

Parameter Changes in obesity

Absorption Changes in gastric motility can alter oral absorptionChanges in body composition

Subcutaneous absorption delayed or incomplete

with increased adipose tissue

Intramuscular injections mistakenly given as

deep subcutaneous injectionsDistribution Little/no change in volume of distribution expected if

Large molecular size

Highly ionized

Highly protein bound

Poorly crosses biological membranes

Increase in volume of distribution expected if

Small molecular size

Minimally ionized

Minimally protein bound

Easily crosses biological membranesMetabolism Increased fatty inltration of liver

Altered blood ow and metabolismChange

in activity level of cytochrome P450 enzymesElimination Variable effects on kidney function

Increased glomerular ltration rate in healthy

obese patients

Possible kidney dysfunction with comorbid

conditions

2014 John Wiley & Sons Ltd Journal of Clinical Pharmacy and Therapeutics, 2014

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Antimicrobials in obesity A. K. Polsoet al.


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Table3.Antibiotics

Title&Author(year)

De

sign&samplesize

Results

Safety

Conclusions

Aminoglycosides

Tobramycin

pharmacokineticsinmorbidly

obesepatients

Blouin(1979)

Single-dosepharmacokinetics

study

Morbidlyobesewomenstatus

post-gastricbypasssurgerygivena

120mgtobramycindose

n=9

MeanrelativeVdwas044L/kg

ba

sedonIBWand020L/kgbased

on

ABW

Not

addressed

58%ofadiposeweightmust

betakeninto

accountto

normalizeVd

inobese

patients

Authorsrecommendbasing

dosingscheduleonIBW

plus58%ofexcessweight

Administrationof

gentamicintoobesepatients

Korsager(1980)

Single-dosepharmacokineticstudy

Adult,obesepatientswith>50%

excessweighttreatedwithgenta-

micinforbacterialinfectionscom-

paredtonormal-weightpatients

Gentamicin0813mg/kg

(cappedat120mg)

n=17

Uptakeofgentamicininadipose

tis

suefoundtobe437%ofuptake

in

ABW

ofnormal-weightpatients

AverageapparentVdinobeseand

no

rmalpatientswas177%and

23

0%,respectively

Se

rumhalf-lifevaluesinobeseand

no

rmal-weightgroupsunchanged

Thre

epatientswere

excludedduetobaseline

abnormalserumcreatinine

Authorsrecommendusing

AdjBW

todetermineproper

gentamicindose

Ad-

jBW

=(ABW

IBW)9

43

7%+IBW

Aminoglycosidedosingin

obesepuerperalwomen

Gibbs(1985)

Non-randomized,prospective

study

Obesepuerperalwomen(ABW

30%largerthandesirableweight)

treatedforendometritis

Dosedwith15mg/kgevery8h,

withonegroupdosedbasedon

AdjBW

andanothergroupdosed

onABW

(cappedat150mgper

dose)

n=27

Averagepeakserumconcentration

of

47and55lg/mLinadjusted

an

dnon-adjusteddosinggroups,

respectively(non-signicantdiffer-

en

t,P-valuenotreported)

Nopatientshowedsignsof

nephrotoxicity

Noserumlevelexceeded

10l

g/mL

Dosesofgentamicinortob-

ramycindon

otneedtobe

adjustedforexcessweight

initially,althoughdrug

concentration

monitoring

wouldberec

ommended

Amikacinpharmacokinetics

inmorbidlyobesepatients

Bauer(1980)

Single-dosekineticsstudy

Morbidlyobesepost-operative

gastricbypasspatientsgivenone

doseof1250mgIVamikacin

n=7

Co

rrectionfactorof038normal-

izedVdinobesepatients

Not

addressed

Peakamikacinserumlevels

canbepredic

tedbestwhen

Vdbasedon

IBW

plus

correctionfac

torof38%of

fatweightis

used (c

ontinued)

2014 John Wiley & Sons Ltd Journal of Clinical Pharmacy and Therapeutics, 2014

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Antimicrobials in obesity A. K. Polsoet al.


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Table3(continued)

Title&Author(year)

Design&samplesize

Results

Safety

Conclusions

Inuenceofweighton

aminoglycoside

pharmacokineticsinnormal-

weightandmorbidlyobese

patients

Bauer(1983)

Matched,controlledmultiple-dose

pharmacokineticstudy

Normal-weightandmorbidly

obesepatientswithnormalrenal

functionanddocumentedgram

negativeinfection

Dailydosesdividedevery8h:

540mggentamicin,690mgtobra-

mycin,1970mgamikacin

n=60

Half-lifeunchangedbetween

groups

Gentamicin:Vdof017and025L/

kg

ABW

(P

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