antibiotik profilaksis ASHP

ASHP RePoRt Antimicrobial prophylaxis

195Am J Health-Syst PharmVol 70 Feb 1, 2013

A S H P r e P o r t

Clinical practice guidelines for antimicrobial prophylaxis in surgery

Dale W. Bratzler, e. Patchen Dellinger, Keith M. Olsen, trish M. Perl, Paul g. auWaerter, Maureen K. BOlOn, DOuglas n. Fish, lena M. naPOlitanO, rOBert g. saWyer, DOuglas slain,

JaMes P. steinBerg, anD rOBert a. Weinstein

Am J Health-Syst Pharm. 2013; 70:195-283

These guidelines were developed jointly by the American Society of Health-System Pharmacists (ASHP), the Infectious Diseases So-ciety of America (IDSA), the Surgi-cal Infection Society (SIS), and the Society for Healthcare Epidemiology of America (SHEA). This work rep-resents an update to the previously published ASHP Therapeutic Guide-lines on Antimicrobial Prophylaxis in Surgery,1 as well as guidelines from IDSA and SIS.2,3 The guidelines are intended to provide practitioners with a standardized approach to the rational, safe, and effective use of antimicrobial agents for the preven-tion of surgical-site infections (SSIs) based on currently available clinical evidence and emerging issues.

Dale W. Bratzler, D.O., M.P.H., is Professor and Associate Dean, College of Public Health, and Professor, College of Medicine, Okla-homa University Health Sciences Center, Oklahoma City. e. Patchen Dellinger, M.D., is Professor and Vice Chairman, Department of Surgery, and Chief, Division of General Surgery, University of Washington, Seattle. Keith M. Olsen, PharM.D., FCCP, FCCM, is Professor of Pharmacy Practice, Nebraska Medical Center, Omaha. trish M. Perl, M.D., M.sc., is Professor of Medicine, Pathology, and Epidemiology, Johns Hopkins University (JHU), and Senior Epidemiologist, The Johns Hopkins Health System, Baltimore, MD. Paul g. auWaerter, M.D., is Clinical Director and Associate Professor, Division of Infectious Diseases, School of Medicine, JHU. Maureen K. BOlOn, M.D., M.S., is Associate Professor of Medi-cine, Division of Infectious Diseases, Feinberg School of Medicine, Northwestern University, Chicago, IL. DOuglas n. Fish, PharM.D., FCCM, FCCP, BCPS, is Professor and Chair, Department of Clinical Pharmacy, University of Colorado, Anschultz Medical Campus, and

Clinical Specialist, Critical Care/Infectious Diseases, Department of Pharmacy Services, University of Colorado Hospital, Aurora. lena M. naPOlitanO, M.D., FACS, FCCP, FCCM, is Professor of Surgery and Division Chief, Acute Care Surgery, Trauma, Burn, Critical Care, Emergency Surgery, and Associate Chair of Surgery, Critical Care, Department of Surgery, and Director, Surgical Critical Care, Uni-versity of Michigan Health System, Ann Arbor. rOBert g. saWyer, M.D., FACS, FIDSA, FCCM, is Professor of Surgery, Public Health Sciences, and Chief, Division of Acute Care, Surgery and Outcomes Research, University of Virginia Health System, Charlottesville, VA. DOuglas slain, PharM.D., BCPS, FCCP, FASHP, is Associate Professor of Pharmacy and Medicine, West Virginia University, Mor-gantown. JaMes P. steinBerg, M.D., is Professor of Medicine, Divi-sion of Infectious Diseases, Emory University, Atlanta, GA. rOBert a. Weinstein, M.D., is C. Anderson Hedberg MD Professor of Internal Medicine, Rush Medical College, Chicago, and Chairman, Department of Medicine, Cook County Health and Hospital System, Chicago.

Prophylaxis refers to the preven-tion of an infection and can be char-acterized as primary prophylaxis, secondary prophylaxis, or eradica-tion. Primary prophylaxis refers to the prevention of an initial infection. Secondary prophylaxis refers to the prevention of recurrence or reactiva-tion of a preexisting infection. Eradi-cation refers to the elimination of a colonized organism to prevent the development of an infection. These guidelines focus on primary periop-erative prophylaxis.

Guidelines development and use Members of ASHP, IDSA, SIS, and

SHEA were appointed to serve on an expert panel established to ensure the validity, reliability, and utility

of the revised guidelines. The work of the panel was facilitated by fac-ulty of the University of Pittsburgh School of Pharmacy and University of Pittsburgh Medical Center Drug Use and Disease State Management Program who served as contract re-searchers and writers for the project. Panel members and contractors were required to disclose any possible con-flicts of interest before their appoint-ment and throughout the guideline development process. Drafted docu-ments for each surgical procedural section were reviewed by the expert panel and, once revised, were avail-able for public comment on the ASHP website. After additional revi-sions were made to address reviewer comments, the final document was


196 Am J Health-Syst PharmVol 70 Feb 1, 2013

approved by the expert panel and the boards of directors of the above-named organizations.

Strength of evidence and grading of recommendations. The primary literature from the previous ASHP Therapeutic Guidelines on Antimi-crobial Prophylaxis in Surgery1 was reviewed together with the primary literature published between the date of the previous guidelines, 1999, and June 2010, identified by searches of MEDLINE, EMBASE, and the Cochrane Database of Systematic Reviews. Particular attention was paid to study design, with greatest credence given to randomized, con-trolled, double-blind studies. There is a limited number of adequately powered randomized controlled trials evaluating the efficacy of an-timicrobial prophylaxis in surgical procedures. Guidelines develop-ment included consideration of the following characteristics: validity, reliability, clinical applicability, flex-ibility, clarity, and a multidisciplinary nature as consistent with ASHPs philosophy on therapeutic guide-lines.4 The limitations of the evidence base are noted within each individual procedure section of the guidelines. Published guidelines with recommen-dations by experts in a procedure area (e.g., American College of Obstetri-cians and Gynecologists [ACOG]) and noted general guidelines (e.g., Centers for Disease Control and Prevention [CDC], Scottish Intercol-

legiate Guidelines Network, Medical Letter, SIS, SHEA/IDSA) were also considered.2,3,5-11

Recommendations for the use of antimicrobial prophylaxis are graded according to the strength of evidence available. The strength of evidence represents only support for or against prophylaxis and does not apply to the antimicrobial agent, dose, or dosage regimen. Studies supporting the recommendations for the use of antimicrobial therapy were classified as follows:

Level I (evidence from large, well-conducted, randomized, controlled clinical trials or a meta-analysis),

Level II (evidence from small, well-conducted, randomized, controlled clinical trials),

Level III (evidence from well- conducted cohort studies),

Level IV (evidence from well- conducted casecontrol studies),

LevelV(evidence fromuncontrolledstudies that were not well conducted),

Level VI (conflicting evidence that tends to favor the recommendation), or

LevelVII (expert opinion or data ex-trapolated from evidence for general principles and other procedures).

This system has been used by the Agency for Healthcare Research and Quality, and ASHP, IDSA, SIS, and SHEA support it as an acceptable method for organizing strength of

evidence for a variety of therapeutic or diagnostic recommendations.4 Each recommendation was cat-egorized according to the strength of evidence that supports the use or nonuse of antimicrobial prophylaxis as category A (levels IIII), category B (levels IVVI), or category C (level VII).

When higher-level data are not available, a category C recommen-dation represents a consensus of expert panel members based on their clinical experience, extrapolation from other procedures with similar microbial or other clinical features, and available published literature. In these cases, the expert panel also extrapolated general principles and evidence from other procedures. Some recommendations include al-ternative approaches in situations in which panel member opinions were divided.

A major limitation of the available literature on antimicrobial prophy-laxis is the difficulty in establishing significant differences in efficacy between prophylactic antimicrobial agents and controls (including place-bo, no treatment, or other antimicro-bial agents) due to study design and low SSI rates for most procedures. A small sample size increases the likeli-hood of a Type II error; therefore, there may be no apparent difference between the antimicrobial agent and placebo when in fact the antimicro-bial has a beneficial effect.12 A valid

The following individuals are acknowledged for their significant contributions to this manuscript: Sandra I. Berros-Torres, M.D.; Rachel Bongiorno-Karcher, Pharm.D.; Colleen M. Culley, Pharm.D., BCPS; Susan R. Dombrowski, M.S., B.S.Pharm.; and Susan J. Skledar, B.S.Pharm., M.P.H., FASHP.

Financial support provided by Emory University, Johns Hopkins University, Northwestern University, Rush University, University of Colorado, University of Michigan, University of Oklahoma, Univer-sity of Nebraska, University of Virginia, University of Washington, and West Virginia University.

Dr. Bratzler is a consultant for Telligen; Dr. Dellinger has received honoraria for participation on advisory boards and consultation for Merck, Baxter, Ortho-McNeil, Targanta, Schering-Plough, WebEx, Astellas, Durata, Pfizer, Applied Medical, Rib-X, 3M, the American Hospital Association, Premier Inc., Oklahoma Foundation for Medi-cal Quality, and the Hospital Association of New York State; Dr. Perl serves on the advisory boards of Hospira and Pfizer and has received

a grant from Merck; Dr. Auwaerter serves on the advisory panel of Genentech; Dr. Fish serves on the advisory board and speakers bu-reau of Merck; and Dr. Sawyer serves as a consultant for Pfizer, Merck, Wyeth, 3M, and Ethicon and has received an R01 grant from the National Institute of General Medical Sciences and a T32 grant from the National Institute of Allergy and Infectious Diseases. Drs. Bolon, Napolitano, Olsen, Steinberg, Slain, and Weinstein have declared no potential conflicts of interest.

The bibliographic citation for this article is as follows: Bratzler DW, Dellinger EP, Olsen KM et al. Clinical practice guidelines for antimicrobial prophylaxis in surgery. Am J Health-Syst Pharm. 2013; 70:195-283.

Copyright 2013, American Society of Health-System Pharma-cists, Inc. All rights reserved. 1079-2082/13/0201-0195$06.00.

DOI 10.2146/ajhp120568



study is placebo controlled and ran-domized with a sufficient sample in each group to avoid a Type II error. Of note, prophylaxis is recommend-ed in some cases due to the severity of complications of postoperative in-fection (e.g., an infected device that is not easily removable) necessitating precautionary measures despite the lack of statistical support.

Summary of key updates. These guidelines reflect substantial changes from the guidelines published in 1999.1 Highlights of those changes are outlined here.

Preoperative-dose timing. The optimal time for administration of preoperative doses is within 60 min-utes before surgical incision. This is a more-specific time frame than the previously recommended time, which was at induction of anesthe-sia. Some agents, such as fluoro-quinolones and vancomycin, require administration over one to two hours; therefore, the administration of these agents should begin within 120 minutes before surgical incision.

Selection and dosing. Information is included regarding the approach to weight-based dosing in obese pa-tients and the need for repeat doses during prolonged procedures.13-18 Obesity has been linked to an in-creased risk for SSI. The pharma-cokinetics of drugs may be altered in obese patients, so dosage adjust-ments based on body weight may be warranted in these patients. For all patients, intraoperative redosing is needed to ensure adequate serum and tissue concentrations of the antimicrobial if the duration of the procedure exceeds two half-lives of the drug or there is excessive blood loss during the procedure (Table 1). Recommendations for selection of antimicrobial agents for specific surgical procedures and alternative agents (e.g., for patients with aller-gies to b-lactam antimicrobials) are provided in Table 2.

Duration of prophylaxis. New rec-ommendations for a shortened post-

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A A C A C A A A A A A C

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Type

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gent

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le 2

(con

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of

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bst

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with

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and

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t ins

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etro

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pic

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+

met

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pen

em

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olin

, cef

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azol

in +

met

roni

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le, c

efur

oxim

e +

m

etro

nida

zole

, am

pic

illin

sul

bac

tam

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azol

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met

roni

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m

etro

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, am

pic

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bac

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Cef

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efaz

olin

Cef

azol

in, c

efot

etan

, cef

oxiti

n, a

mp

icill

in

sulb

acta

mh

Top

ical

neo

myc

inp

olym

yxin

Bg

ram

icid

in o

r fo

urth

-gen

erat

ion

top

ical

fluo

roqu

inol

ones

(g

atifl

oxac

in o

r mox

iflox

acin

) giv

en a

s 1

drop

ev

ery

515

min

for 5

dos

eso

Add

ition

of c

efaz

olin

100

mg

by s

ubco

njun

ctiv

al

inje

ctio

n or

intr

acam

eral

cef

azol

in 1

2.5

mg

or c

efur

oxim

e 1

mg

at th

e en

d of

pro

cedu

re is

op

tiona

l

Non

e

Cef

azol

in

Met

roni

dazo

le +

am

inog

lyco

side

g or

fluor

oqui

nolo

neh-

j

Clin

dam

ycin

, van

com

ycin

Clin

dam

ycin

+ a

min

ogly

cosi

deg o

r az

treo

nam

or fl

uoro

quin

olon

eh-j ,

met

roni

dazo

le +

am

inog

lyco

side

g or

fluor

oqui

nolo

neh-

j

Non

eC

linda

myc

ind

Clin

dam

ycin

d

Clin

dam

ycin

d

Clin

dam

ycin

,d va

ncom

ycin

d

Clin

dam

ycin

,d va

ncom

ycin

d

Clin

dam

ycin

+ a

min

ogly

cosi

deg

Clin

dam

ycin

or v

anco

myc

in +

am

inog

lyco

side

g or a

ztre

onam

or

fluor

oqui

nolo

neh-

j

Met

roni

dazo

le +

am

inog

lyco

side

g or

fluor

oqui

nolo

neh-

j

Non

e

Non

e

Clin

dam

ycin

,d va

ncom

ycin

d

C A A B C A B A C A A B C A

Cont

inue

d on

nex

t pag

e

Alte

rnat

ive

Age

nts

in P

ts W

ith

b-Lac

tam

Alle

rgy



Type

of P

roce

dure

Reco

mm

ende

d A

gent

sa,b

Tab

le 2

(con

tinue

d)

Stre

ngth

of

Evid

ence

c

Cont

inue

d on

nex

t pag

e

H

ip fr

actu

re re

pai

r

Imp

lant

atio

n of

inte

rnal

fixa

tion

devi

ces (

e.g.

, nai

ls, s

crew

s,

pla

tes,

wire

s)

Tota

l joi

nt re

pla

cem

ent

Uro

logi

c

Low

er tr

act i

nstr

umen

tatio

n w

ith ri

sk fa

ctor

s fo

r inf

ectio

n

(in

clud

es tr

ansr

ecta

l pro

stat

e b

iop

sy)

C

lean

with

out e

ntry

into

urin

ary

trac

t

Invo

lvin

g im

pla

nted

pro

sthe

sis

C

lean

with

ent

ry in

to u

rinar

y tr

act

C

lean

-con

tam

inat

ed

Vasc

ular

p

Hea

rt, l

ung,

hea

rtl

ung

tran

spla

ntat

ionq

H

eart

tran

spla

ntat

ionr

Lu

ng a

nd h

eart

lun

g tr

ansp

lant

atio

nr,s

Live

r tra

nsp

lant

atio

nq,t

Panc

reas

and

pan

crea

ski

dney

tran

spla

ntat

ionr

Cef

azol

inC

efaz

olin

Cef

azol

in

Fluo

roqu

inol

one,

h-j t

rimet

hop

rim

sulfa

met

hoxa

zole

, cef

azol

inC

efaz

olin

(the

add

ition

of a

sin

gle

dose

of a

n am

inog

lyco

side

may

be

reco

mm

ende

d fo

r p

lace

men

t of p

rost

hetic

mat

eria

l [e.

g., p

enile

p

rost

hesi

s])

Cef

azol

in a

min

ogly

cosi

de, c

efaz

olin

a

ztre

onam

, am

pic

illin

sul

bac

tam

Cef

azol

in (t

he a

dditi

on o

f a s

ingl

e do

se o

f an

amin

ogly

cosi

de m

ay b

e re

com

men

ded

for

pla

cem

ent o

f pro

sthe

tic m

ater

ial [

e.g.

, pen

ile

pro

sthe

sis]

)C

efaz

olin

+ m

etro

nida

zole

, cef

oxiti

n

Cef

azol

in

Cef

azol

in

Cef

azol

in

Pip

erac

illin

taz

obac

tam

, cef

otax

ime

+ a

mp

icill

in

Cef

azol

in, fl

ucon

azol

e (fo

r pat

ient

s at

hig

h ris

k of

fung

al in

fect

ion

[e.g

., th

ose

with

ent

eric

dr

aina

ge o

f the

pan

crea

s])

Cef

azol

in

Clin

dam

ycin

,d va

ncom

ycin

d

Clin

dam

ycin

,d va

ncom

ycin

d

Clin

dam

ycin

,d va

ncom

ycin

d

Am

inog

lyco

side

g with

or w

ithou

t cl

inda

myc

inC

linda

myc

in,d

vanc

omyc

ind

Clin

dam

ycin

a

min

ogly

cosi

de

or a

ztre

onam

, van

com

ycin

amin

ogly

cosi

de o

r azt

reon

amFl

uoro

quin

olon

e,h-

j am

inog

lyco

side

g w

ith o

r with

out c

linda

myc

in

Fluo

roqu

inol

one,

h-j a

min

ogly

cosi

deg +

m

etro

nida

zole

or c

linda

myc

inC

linda

myc

in,d

vanc

omyc

ind

Clin

dam

ycin

,d va

ncom

ycin

d

Clin

dam

ycin

,d va

ncom

ycin

d

Clin

dam

ycin

or v

anco

myc

in +

am

inog

lyco

side

g or

azt

reon

am o

r flu

oroq

uino

lone

h-j

Clin

dam

ycin

or v

anco

myc

in +

am

inog

lyco

side

g or a

ztre

onam

or

fluor

oqui

nolo

neh-

j

Clin

dam

ycin

or v

anco

myc

in +

am

inog

lyco

side

g or a

ztre

onam

or

fluor

oqui

nolo

neh-

j

A C A A A A A A A

A (b

ased

on

card

iac

pro

cedu

res)

A (b

ased

on

card

iac

pro

cedu

res)

B A A

Alte

rnat

ive

Age

nts

in P

ts W

ith

b-Lac

tam

Alle

rgy



Type

of P

roce

dure

Reco

mm

ende

d A

gent

sa,b

Tab

le 2

(con

tinue

d)

Stre

ngth

of

Evid

ence

c

Plas

tic s

urge

ry

Cle

an w

ith ri

sk fa

ctor

s or

cle

an-c

onta

min

ated

Cef

azol

in, a

mp

icill

ins

ulb

acta

mC

linda

myc

in,d

vanc

omyc

ind

C

a The

ant

imic

rob

ial a

gent

sho

uld

be

star

ted

with

in 6

0 m

inut

es b

efor

e su

rgic

al in

cisi

on (1

20 m

inut

es fo

r va

ncom

ycin

or

fluor

oqui

nolo

nes)

. Whi

le s

ingl

e-do

se p

rop

hyla

xis

is u

sual

ly s

uffici

ent,

the

dura

tion

of p

rop

hyla

xis

for

all p

roce

dure

s sh

ould

be

less

tha

n 24

hou

rs. I

f an

agen

t w

ith a

sho

rt h

alf-

life

is u

sed

(e.g

., ce

fazo

lin, c

efox

itin)

, it

shou

ld b

e re

adm

inis

tere

d if

the

pro

cedu

re d

urat

ion

exce

eds

the

reco

mm

ende

d re

dosi

ng in

terv

al (f

rom

the

tim

e of

initi

atio

n of

the

pre

oper

ativ

e do

se [s

ee T

able

1])

. Rea

dmin

istr

atio

n m

ay a

lso

be

war

rant

ed if

pro

long

ed o

r ex

cess

ive

ble

edin

g oc

curs

or

if th

ere

are

othe

r fa

ctor

s th

at m

ay s

hort

en t

he h

alf-

life

of t

he p

rop

hyla

ctic

age

nt (e

.g.,

exte

nsiv

e b

urns

). Re

adm

inis

trat

ion

may

not

be

war

rant

ed in

pat

ient

s in

who

m th

e ha

lf-lif

e of

the

agen

t may

be

pro

long

ed (e

.g.,

pat

ient

s w

ith re

nal i

nsuffi

cien

cy o

r fai

lure

).bFo

r pat

ient

s kn

own

to b

e co

loni

zed

with

met

hici

llin-

resi

stan

t Sta

phyl

ococ

cus a

ureu

s, it

is re

ason

able

to a

dd a

sin

gle

pre

oper

ativ

e do

se o

f van

com

ycin

to th

e re

com

men

ded

agen

t(s)

. cSt

reng

th o

f evi

denc

e th

at s

upp

orts

the

use

or

nonu

se o

f pro

phy

laxi

s is

cla

ssifi

ed a

s A

(lev

els

IIII

), B

(leve

ls IV

VI),

or

C (l

evel

VII)

. Lev

el I

evid

ence

is fr

om la

rge,

wel

l-con

duct

ed, r

ando

miz

ed c

ontr

olle

d cl

inic

al t

rials

. Lev

el II

ev

iden

ce is

from

sm

all,

wel

l-con

duct

ed, r

ando

miz

ed c

ontr

olle

d cl

inic

al t

rials

. Lev

el II

I evi

denc

e is

from

wel

l-con

duct

ed c

ohor

t st

udie

s. L

evel

IV e

vide

nce

is fr

om w

ell-c

ondu

cted

cas

eco

ntro

l stu

dies

. Lev

el V

evi

denc

e is

from

un

cont

rolle

d st

udie

s th

at w

ere

not w

ell c

ondu

cted

. Lev

el V

I evi

denc

e is

con

flict

ing

evid

ence

that

tend

s to

favo

r the

reco

mm

enda

tion.

Lev

el V

II ev

iden

ce is

exp

ert o

pin

ion.

d For

pro

cedu

res

in w

hich

pat

hoge

ns o

ther

tha

n st

aphy

loco

cci a

nd s

trep

toco

cci a

re li

kely

, an

addi

tiona

l age

nt w

ith a

ctiv

ity

agai

nst

thos

e p

atho

gens

cou

ld b

e co

nsid

ered

. For

exa

mp

le, i

f the

re a

re s

urve

illan

ce d

ata

show

ing

that

gra

m-n

egat

ive

orga

nism

s ar

e a

caus

e of

sur

gica

l-site

infe

ctio

ns (S

SIs)

for t

he p

roce

dure

, pra

ctiti

oner

s m

ay c

onsi

der c

omb

inin

g cl

inda

myc

in o

r van

com

ycin

with

ano

ther

age

nt (c

efaz

olin

if th

e p

atie

nt is

not

b-la

ctam

alle

rgic

; az

treo

nam

, gen

tam

icin

, or s

ingl

e-do

se fl

uoro

quin

olon

e if

the

pat

ient

is b-

lact

am a

llerg

ic).

e Pro

phy

laxi

s sh

ould

be

cons

ider

ed fo

r p

atie

nts

at h

ighe

st r

isk

for

pos

top

erat

ive

gast

rodu

oden

al in

fect

ions

, suc

h as

tho

se w

ith in

crea

sed

gast

ric p

H (e

.g.,

thos

e re

ceiv

ing

hist

amin

e H

2-re

cep

tor

anta

goni

sts

or p

roto

n-p

ump

in

hib

itors

), ga

stro

duod

enal

per

fora

tion,

dec

reas

ed g

astr

ic m

otili

ty, g

astr

ic o

utle

t ob

stru

ctio

n, g

astr

ic b

leed

ing,

mor

bid

ob

esit

y, o

r can

cer.

Ant

imic

rob

ial p

rop

hyla

xis

may

not

be

need

ed w

hen

the

lum

en o

f the

inte

stin

al tr

act i

s no

t ent

ered

. f C

onsi

der a

dditi

onal

ant

imic

rob

ial c

over

age

with

infe

cted

bili

ary

trac

t. Se

e th

e b

iliar

y tr

act p

roce

dure

s se

ctio

n of

this

art

icle

.g G

enta

mic

in o

r tob

ram

ycin

.h D

ue to

incr

easi

ng re

sist

ance

of E

sche

richi

a co

li to

fluo

roqu

inol

ones

and

am

pic

illin

sul

bac

tam

, loc

al p

opul

atio

n su

scep

tibili

ty p

rofil

es s

houl

d b

e re

view

ed p

rior t

o us

e.i C

ipro

floxa

cin

or le

voflo

xaci

n.j F

luor

oqui

nolo

nes

are

asso

ciat

ed w

ith a

n in

crea

sed

risk

of t

endo

nitis

and

ten

don

rup

ture

in a

ll ag

es. H

owev

er, t

his

risk

wou

ld b

e ex

pec

ted

to b

e qu

ite s

mal

l with

sin

gle-

dose

ant

ibio

tic p

rop

hyla

xis.

Alt

houg

h th

e us

e of

flu

oroq

uino

lone

s m

ay b

e ne

cess

ary

for s

urgi

cal a

ntib

iotic

pro

phy

laxi

s in

som

e ch

ildre

n, th

ey a

re n

ot d

rugs

of fi

rst c

hoic

e in

the

ped

iatr

ic p

opul

atio

n du

e to

an

incr

ease

d in

cide

nce

of a

dver

se e

vent

s as

com

par

ed w

ith c

ontr

ols

in s

ome

clin

ical

tria

ls.

k Cef

tria

xone

use

sho

uld

be

limite

d to

pat

ient

s re

quiri

ng a

ntim

icro

bia

l tre

atm

ent f

or a

cute

cho

lecy

stiti

s or

acu

te b

iliar

y tr

act i

nfec

tions

whi

ch m

ay n

ot b

e de

term

ined

prio

r to

inci

sion

, not

pat

ient

s un

derg

oing

cho

lecy

stec

tom

y fo

r non

infe

cted

bili

ary

cond

ition

s, in

clud

ing

bili

ary

colic

or d

yski

nesi

a w

ithou

t inf

ectio

n. lFa

ctor

s th

at i

ndic

ate

a hi

gh r

isk

of i

nfec

tious

com

plic

atio

ns i

n la

par

osco

pic

cho

lecy

stec

tom

y in

clud

e em

erge

ncy

pro

cedu

res,

dia

bet

es, l

ong

pro

cedu

re d

urat

ion,

int

raop

erat

ive

gallb

ladd

er r

uptu

re, a

ge o

f >

70 y

ears

, co

nver

sion

fro

m la

par

osco

pic

to

open

cho

lecy

stec

tom

y, A

mer

ican

Soc

iety

of

Ane

sthe

siol

ogis

ts c

lass

ifica

tion

of 3

or

grea

ter,

epis

ode

of c

olic

with

in 3

0 da

ys b

efor

e th

e p

roce

dure

, rei

nter

vent

ion

in le

ss t

han

one

mon

th f

or

noni

nfec

tious

com

plic

atio

n, a

cute

cho

lecy

stiti

s, b

ile s

pill

age,

jaun

dice

, pre

gnan

cy, n

onfu

nctio

ning

gal

lbla

dder

, im

mun

osup

pre

ssio

n, a

nd in

sert

ion

of p

rost

hetic

dev

ice.

Bec

ause

a n

umb

er o

f the

se ri

sk fa

ctor

s ar

e no

t pos

sib

le to

de

term

ine

bef

ore

surg

ical

inte

rven

tion,

it m

ay b

e re

ason

able

to g

ive

a si

ngle

dos

e of

ant

imic

rob

ial p

rop

hyla

xis

to a

ll p

atie

nts

unde

rgoi

ng la

par

osco

pic

cho

lecy

stec

tom

y.m

For m

ost p

atie

nts,

a m

echa

nica

l bow

el p

rep

arat

ion

com

bin

ed w

ith o

ral n

eom

ycin

sul

fate

plu

s or

al e

ryth

rom

ycin

bas

e or

with

ora

l neo

myc

in s

ulfa

te p

lus

oral

met

roni

dazo

le s

houl

d b

e gi

ven

in a

dditi

on to

i.v.

pro

phy

laxi

s.n W

here

ther

e is

incr

easi

ng re

sist

ance

to fi

rst-

and

sec

ond-

gene

ratio

n ce

phal

ospo

rins

amon

g gr

am-n

egat

ive

isol

ates

from

SSI

s, a

sing

le d

ose

of c

eftr

iaxo

ne p

lus

met

roni

dazo

le m

ay b

e pr

efer

red

over

the

rout

ine

use

of c

arba

pene

ms.

o The

nec

essi

ty o

f con

tinui

ng to

pic

al a

ntim

icro

bia

ls p

osto

per

ativ

ely

has

not b

een

esta

blis

hed.

pPr

ophy

laxi

s is

not

rout

inel

y in

dica

ted

for b

rach

ioce

pha

lic p

roce

dure

s. A

ltho

ugh

ther

e ar

e no

dat

a in

sup

por

t, p

atie

nts

unde

rgoi

ng b

rach

ioce

pha

lic p

roce

dure

s in

volv

ing

vasc

ular

pro

sthe

ses

or p

atch

imp

lant

atio

n (e

.g.,

caro

tid

enda

rter

ecto

my)

may

ben

efit f

rom

pro

phy

laxi

s.

q The

se g

uide

lines

refl

ect

reco

mm

enda

tions

for

per

iop

erat

ive

antib

iotic

pro

phy

laxi

s to

pre

vent

SSI

s an

d do

not

pro

vide

rec

omm

enda

tions

for

pre

vent

ion

of o

pp

ortu

nist

ic in

fect

ions

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pediatric-specific prophylaxis data are sparse, available data have been evaluated and are presented in some of the procedure-specific sections of these guidelines. Selection of antimicrobial prophylactic agents mirrors that in adult guidelines, with the agents of choice being first- and second-generation cephalosporins, reserving the use of vancomycin for patients with documented b-lactam allergies.19,20 While the use of a pen-icillin with a b-lactamase inhibitor in combination with cefazolin or vancomycin and gentamicin has also been studied in pediatric patients, the number of patients included in these evaluations remains small.20-23 As with adults, there is little evidence supporting the use of vancomycin, alone or in combination with other antimicrobials, for routine perioper-ative antimicrobial prophylaxis in in-stitutions that have a high prevalence of methicillin-resistant Staphylococ-cus aureus (MRSA). Vancomycin may be considered in children known to be colonized with MRSA and, in one retrospective historical cohort study, was shown to decrease MRSA infections.21 Mupirocin use has been studied in and is efficacious in chil-dren colonized with MRSA, but there are limited data supporting its use perioperatively.24-30 However, there is little reason to think that the impact and effect would be any different in children, so its use may be justified. Additional studies in this setting are needed to establish firm guidelines.

Unless noted in specific sections, all recommendations for adults are the same for pediatric patients, except for dosing. In most cases, the data in pediatric patients are limited and have been extrapolated from adult data; therefore, nearly all pediatric recommendations are based on expert opinion. In some sections, pediatric efficacy data do not exist and thus are not addressed in these guidelines. Fluoroquino-lones should not be routinely used for surgical prophylaxis in pediatric

patients because of the potential for toxicity in this population. The same principle of preoperative dosing within 60 minutes before incision has been applied to pediatric patients.20-23 Additional intraoperative dosing may be needed if the duration of the procedure exceeds two half-lives of the antimicrobial agent or there is excessive blood loss during the procedure.19,21 As with adult patients, single-dose prophylaxis is usually sufficient. If antimicrobial prophy-laxis is continued postoperatively, the duration should be less than 24 hours, regardless of the presence of intravascular catheters or indwelling drains.19,22,23,31,32 There are sufficient pharmacokinetic studies of most agents to recommend pediatric dos-ages that provide adequate systemic exposure and, presumably, efficacy comparable to that demonstrated in adults. Therefore, the pediatric dos-ages provided in these guidelines are based largely on pharmacokinetic data and the extrapolation of adult efficacy data to pediatric patients. Because few clinical trials have been conducted in pediatric surgical pa-tients, strength of evidence criteria have not been applied to these rec-ommendations. With few exceptions (e.g., aminoglycoside dosages), pe-diatric dosages should not exceed the maximum adult recommended dos-ages. Generally, if dosages are calculat-ed on a milligram-per-kilogram basis for children weighing more than 40 kg, the calculated dosage will exceed the maximum recommended dosage for adults; adult dosages should there-fore be used.

Patients with prosthetic implants. For patients with existing prosthetic implants who undergo an invasive procedure, there is no evidence that antimicrobial prophylaxis prevents infections of the implant. However, updated guidelines from the Ameri-can Heart Association (AHA) suggest that prophylaxis may be justified in a limited subset of patients for the prevention of endocarditis.11

Common principles and procedure-specific guidelines. The Common Principles section has been devel-oped to provide information com-mon to many surgical procedures. These principles are general recom-mendations based on currently avail-able data at the time of publication that may change over time; therefore, these principles need to be applied with careful attention to each clinical situation. Detailed information per-tinent to specific surgical procedures is included in the procedure-specific sections of these guidelines.

In addition to patient- and procedure-specific considerations, several institution-specific factors must be considered by practitioners before instituting these guidelines. The availability of antimicrobial agents at the institution may be re-stricted by local antimicrobial-use policy or lack of approval for use by regulatory authorities. Medications that are no longer available or not ap-proved for use by the Food and Drug Administration (FDA) are so noted. Local resistance patterns should also be considered in selecting antimicro-bial agents and are discussed in the colonization and resistance patterns section of the Common Principles section.

Requirements for effective surgical prophylaxis

Appendix A lists the wound clas-sification criteria currently used by the CDC National Healthcare Safety Network (NHSN) and Healthcare Infection Control Practices Advisory Committee (HICPAC).33-35

Criteria for defining an SSI have also been established by NHSN (Ap-pendix B).8,36 These definitions as-sist in evaluating the importance of providing antimicrobial prophylaxis and the potential consequences of infection, including the need for treatment. Some criteria vary slightly by procedure.

Although antimicrobial prophy-laxis plays an important role in reduc-



ing the rate of SSIs, other factors such as attention to basic infection-control strategies,37 the surgeons experience and technique, the duration of the procedure, hospital and operating-room environments, instrument-sterilization issues, preoperative prep-aration (e.g., surgical scrub, skin antisepsis, appropriate hair removal), perioperative management (tempera-ture and glycemic control), and the underlying medical condition of the patient may have a strong impact on SSI rates.5,8 These guidelines recognize the importance of these other factors but do not include a discussion of or any recommendations regarding these issues beyond the optimal use of prophylactic antimicrobial agents. Patient-related factors associated with an increased risk of SSI include extremes of age, nutritional status, obesity, diabetes mellitus, tobacco use, coexistent remote body-site infec-tions, altered immune response, cor-ticosteroid therapy, recent surgical procedure, length of preoperative hospitalization, and colonization with microorganisms. Antimicro-bial prophylaxis may be justified for any procedure if the patient has an underlying medical condition as-sociated with a high risk of SSI or if the patient is immunocompromised (e.g., malnourished, neutrope-nic, receiving immunosuppressive agents).

Antimicrobial prophylaxis may be beneficial in surgical procedures associated with a high rate of infec-tion (i.e., clean-contaminated or contaminated procedures) and in certain clean procedures where there are severe consequences of infection (e.g., prosthetic implants), even if in-fection is unlikely. While prophylac-tic antimicrobials are not indicated for some clean surgical procedures,8 available data suggest that the rela-tive risk reduction of SSI from the use of antimicrobial prophylaxis is the same in clean and in higher-risk procedures.38 The decision to use prophylaxis depends on the cost of

treating and the morbidity associ-ated with infection compared with the cost and morbidity associated with using prophylaxis. Antimicrobial prophylaxis is justified for most clean-contaminated procedures. The use of antimicrobial agents for dirty pro-cedures (Appendix A) or established infections is classified as treatment of presumed infection, not prophylaxis. See the procedure-specific sections for detailed recommendations.

Quality-improvement efforts. National, state, local, and institu-tional groups have developed and implemented collaborative efforts to improve the appropriateness of sur-gical antimicrobial prophylaxis. Vari-ous process and outcomes measures are employed, and results are dis-seminated. Institutional epidemiol-ogy and infection-control programs, state-based quality-improvement campaigns (e.g., the Michigan Sur-gical Quality Collaborative, the Washington State Surgical Clinical Outcomes Assessment Program39,40), CDC, NHSN, the National Surgical Quality Improvement Program, the Joint Commission, and the National Quality Forum have been instru-mental in developing programs to prevent SSIs.

Over the past decade or more, several organizations, payers, and government agencies, including the Centers for Medicare and Medicaid Services (CMS), have established national quality-improvement initia-tives to further improve the safety and outcomes of health care, includ-ing surgery.41-47 One area of focus in these initiatives for patients un-dergoing surgical procedures is the prevention of SSIs. The performance measures used, data collection and reporting requirements, and finan-cial implications vary among the ini-tiatives. The Surgical Care Improve-ment Project (SCIP) began in 2002 as the Surgical Infection Prevention (SIP) project, focusing on the tim-ing, selection, and duration of pro-phylactic antimicrobial agents.41,42

The SIP project was expanded to SCIP to include additional process measures surrounding patient safety and care during surgical procedures, including glucose control, venous thromboembolism prophylaxis, hair removal, and temperature control. Similar measures have been adopted by the Joint Commission.43 The Phy-sicians Quality Reporting System was established in 2006 to provide finan-cial incentives to physicians meeting performance standards for quality measures, including surgery-related measures similar to those reported for SCIP and the Joint Commis-sion.44 Data are required to be col-lected by institutions and reported to payers.42,44,46 Data for CMS and the Physicians Quality Reporting System measures are displayed on public websites to allow consumers to com-pare performance among hospitals. Institutional data collection and reporting are required, with financial incentives tied to performance to varying degrees, including payment for reporting, payment increases for meeting or exceeding minimum levels of performance, payment re-duction for poor performance, and lack of payment for the development of surgical complications, such as mediastinitis.

Quality-improvement initiatives and mandated performance report-ing are subject to change, so readers of these guidelines are advised to consult their local or institutional quality-improvement departments for new developments in require-ments for measures and data report-ing that apply to their practice.

Cost containment. Few pharma-coeconomic studies have addresed surgical antimicrobial prophylaxis; therefore, a cost-minimization ap-proach was employed in developing these guidelines. The antimicrobial agent recommendations are based primarily on efficacy and safety. In-dividual institutions must consider their acquisition costs when imple-menting these guidelines.



Additional cost savings may be realized through collaborative man-agement by pharmacists and sur-geons to select the most cost-effective agent and minimize or eliminate postoperative dosing.48-50 The use of standardized antimicrobial order sets, automatic stop-order programs, and educational initiatives has been shown to facilitate the adoption of guidelines for surgical antimicrobial prophylaxis.51-58

Common principlesIdeally, an antimicrobial agent

for surgical prophylaxis should (1) prevent SSI, (2) prevent SSI-related morbidity and mortality, (3) reduce the duration and cost of health care (when the costs associated with the management of SSI are considered, the cost-effectiveness of prophylaxis becomes evident),51,52 (4) produce no adverse effects, and (5) have no adverse consequences for the mi-crobial flora of the patient or the hospital.53 To achieve these goals, an antimicrobial agent should be (1) ac-tive against the pathogens most likely to contaminate the surgical site, (2) given in an appropriate dosage and at a time that ensures adequate serum and tissue concentrations during the period of potential contamination, (3) safe, and (4) administered for the shortest effective period to minimize adverse effects, the development of resistance, and costs.8,59,60

The selection of an appropriate antimicrobial agent for a specific patient should take into account the characteristics of the ideal agent, the comparative efficacy of the antimicro-bial agent for the procedure, the safety profile, and the patients medication allergies. A full discussion of the safety profile, including adverse events, drug interactions, contraindications, and warnings, for each antimicrobial agent is beyond the scope of these guidelines. Readers of these guidelines should review the FDA-approved prescribing information and published data for specific antimicrobial agents before

use. For most procedures, cefazolin is the drug of choice for prophylaxis because it is the most widely studied antimicrobial agent, with proven ef-ficacy. It has a desirable duration of action, spectrum of activity against organisms commonly encountered in surgery, reasonable safety, and low cost. There is little evidence to suggest that broad-spectrum antimicrobial agents (i.e., agents with broad in vitro antibacterial activity) result in lower rates of postoperative SSI compared with older antimicrobial agents with a narrower spectrum of activity. How-ever, comparative studies are limited by small sample sizes, resulting in dif-ficulty detecting a significant differ-ence between antimicrobial agents; therefore, antimicrobial selection is based on cost, safety profile, ease of ad-ministration, pharmacokinetic profile, and bactericidal activity.

Common surgical pathogensThe agent chosen should have

activity against the most common surgical-site pathogens. The pre-dominant organisms causing SSIs after clean procedures are skin flora, includ-ing S. aureus and coagulase-negative staphylococci (e.g., Staphylococcus epidermidis).61 In clean-contaminated procedures, including abdominal pro-cedures and heart, kidney, and liver transplantations, the predominant organisms include gram-negative rods and enterococci in addition to skin flora. Additional details on common organisms can be found in procedure-specific sections of these guidelines.

Recommendations for the selec-tion of prophylactic antimicrobials for various surgical procedures are provided in Table 2. Adult and pe-diatric dosages are included in Table 1. Agents that are FDA-approved for use in surgical antimicrobial prophy-laxis include cefazolin, cefuroxime, cefoxitin, cefotetan, ertapenem, and vancomycin.62-67

Trends in microbiology. The causative pathogens associated with SSIs in U.S. hospitals have changed

over the past two decades. Analysis of National Nosocomial Infections Sur-veillance (NNIS) System data found that the percentage of SSIs caused by gram-negative bacilli decreased from 56.5% in 1986 to 33.8% in 2003.68 S. aureus was the most common pathogen, causing 22.5% of SSIs during this time period. NHSN data from 2006 to 2007 revealed that the proportion of SSIs caused by S. au-reus increased to 30%, with MRSA comprising 49.2% of these isolates.61 In a study of patients readmitted to U.S. hospitals between 2003 and 2007 with a culture-confirmed SSI, the proportion of infections caused by MRSA increased significantly from 16.1% to 20.6% (p < 0.0001).69

MRSA infections were associated with higher mortality rates, longer hospital stays, and higher hospital costs compared with other infections.

Spectrum of activity. Antimi-crobial agents with the narrowest spectrum of activity required for efficacy in preventing infection are recommended in these guidelines. Alternative antimicrobial agents with documented efficacy are also listed herein. Individual health sys-tems must consider local resistance patterns of organisms and overall SSI rates at their site when adopting these recommendations. Resistance patterns from organisms causing SSIsin some cases procedure-specific resistance patternsshould take precedence over hospitalwide antibiograms.

Vancomycin. In 1999, HICPAC, an advisory committee to CDC and the Secretary of the Department of Health and Human Services, col-laborated with other major organiza-tions to develop recommendations for preventing and controlling van-comycin resistance.70 The recom-mendations are echoed by these and other guidelines.6,7,41,71 Routine use of vancomycin prophylaxis is not recommended for any procedure.8 Vancomycin may be included in the regimen of choice when a cluster of



MRSA cases (e.g., mediastinitis after cardiac procedures) or methicillin-resistant coagulase-negative staphy-lococci SSIs have been detected at an institution. Vancomycin prophylaxis should be considered for patients with known MRSA colonization or at high risk for MRSA colonization in the absence of surveillance data (e.g., patients with recent hospitalization, nursing-home residents, hemodi-alysis patients).5,41,72 In institutions with SSIs attributable to community- associated MRSA, antimicrobial agents with known in vitro activity against this pathogen may be consid-ered as an alternative to vancomycin.

Each institution is encouraged to develop guidelines for the proper use of vancomycin. Although van-comycin is commonly used when the risk for MRSA is high, data sug-gest that vancomycin is less effective than cefazolin for preventing SSIs caused by methicillin-susceptible S. aureus (MSSA).73,74 For this reason, vancomycin is used in combination with cefazolin at some institutions with both MSSA and MRSA SSIs. For procedures in which pathogens other than staphylococci and strep-tococci are likely, an additional agent with activity against those pathogens should be considered. For example, if there are surveillance data showing that gram-negative organisms are a cause of SSIs for the procedure, prac-titioners may consider combining vancomycin with another agent (cef-azolin if the patient does not have a b-lactam allergy; an aminoglycoside [gentamicin or tobramycin], aztreo-nam, or single-dose fluoroquinolone if the patient has a b-lactam allergy). The use of vancomycin for MRSA prophylaxis does not supplant the need for routine surgical prophylaxis appropriate for the type of proce-dure. When vancomycin is used, it can almost always be used as a single dose due to its long half-life.

Colonization and resistance. A national survey determined that S. aureus nasal colonization in the

general population decreased from 32.4% in 200102 to 28.6% in 200304 (p < 0.01), whereas the prevalence of colonization with MRSA increased from 0.8% to 1.5% (p < 0.05) during the same time periods.75 Coloniza-tion with MRSA was independently associated with health care exposure among men, having been born in the United States, age of >60 years, diabetes, and poverty among women. Similarly, children are colonized with S. aureus and MRSA, but coloniza-tion varies by age. Children under 5 years of age have the highest rates, mirroring rates seen in patients over age 60 years.76 The rates drop in children between 5 and 14 years of age and gradually increase to rates seen in the adult population. Lo et al.77 reported that in a large cohort of children, 28.1% were colonized with S. aureus between 2004 and 2006. Between 2007 and 2009, 23.3% of children were colonized with S. au-reus, but the proportion of children colonized with MRSA had increased from 8.1% in 2004 to 15.1% in 2009.

Surgical antimicrobial prophylaxis can alter individual and institutional bacterial flora, leading to changes in colonization rates and increased bacterial resistance.78-84 Surgical pro-phylaxis can also predispose patients to Clostridium difficile-associated colitis.81 Risk factors for development of C. difficile-associated colitis include longer duration of prophylaxis or therapy and use of multiple antimicro-bial agents.85 Limiting the duration of antimicrobial prophylaxis to a single preoperative dose can reduce the risk of C. difficile disease.

The question of what antimicro-bial surgical prophylaxis to use for patients known to be colonized or recently infected with multidrug-resistant pathogens cannot be an-swered easily or in a manner that can be applied uniformly to all patient scenarios. Whether prophy-laxis should be expanded to provide coverage for these pathogens de-pends on many factors, including the

pathogen, its antimicrobial suscepti-bility profile, the host, the procedure to be performed, and the proximity of the likely reservoir of the pathogen to the incision and operative sites. While there is no evidence on the management of surgical antimicro-bial prophylaxis in a patient with past infection or colonization with a resistant gram-negative pathogen, it is logical to provide prophylaxis with an agent active against MRSA for any patient known to be colonized with this gram-positive pathogen who will have a skin incision; specific prophy-laxis for a resistant gram-negative pathogen in a patient with past in-fection or colonization with such a pathogen may not be necessary for a purely cutaneous procedure. Similarly, a patient colonized with vancomycin-resistant enterococci (VRE) should receive prophylaxis ef-fective against VRE when undergoing liver transplantation but probably not when undergoing an umbilical hernia repair without mesh place-ment. Thus, patients must be treated on a case-by-case basis, taking into account multiple considerations.

Patients receiving therapeutic antimicrobials for a remote infection before surgery should also be given antimicrobial prophylaxis before surgery to ensure adequate serum and tissue levels of antimicrobials with activity against likely pathogens for the duration of the operation. If the agents used therapeutically are appropriate for surgical prophylaxis, administering an extra dose within 60 minutes before surgical incision is sufficient. Otherwise, the antimi-crobial prophylaxis recommended for the planned procedure should be used. For patients with indwelling tubes or drains, consideration may be given to using prophylactic agents active against pathogens found in these devices before the procedure, even though therapeutic treatment for pathogens in drains is not in-dicated at other times. For patients with chronic renal failure receiving



vancomycin, a preoperative dose of cefazolin should be considered in-stead of an extra dose of vancomycin, particularly if the probable patho-gens associated with the procedure are gram-negative. In most circum-stances, elective surgery should be postponed when the patient has an infection at a remote site.

Allergy to b-lactam antimicrobi-als. Allergy to b-lactam antimicro-bials may be a consideration in the selection of surgical prophylaxis. The b-lactam antimicrobials, including cephalosporins, are the mainstay of surgical antimicrobial prophylaxis and are also the most commonly im-plicated drugs when allergic reac-tions occur. Because the predominant organisms in SSIs after clean proce-dures are gram-positive, the inclusion of vancomycin may be appropriate for a patient with a life-threatening allergy to b-lactam antimicrobials.

Although true Type 1 (immuno-globulin E [IgE]-mediated) cross-allergic reactions between penicillins, cephalosporins, and carbapenems are uncommon, cephalosporins and carbapenems should not be used for surgical prophylaxis in patients with documented or presumed IgE- mediated penicillin allergy. Confu-sion about the definition of true allergy among patients and practi-tioners leads to recommendations for alternative antimicrobial therapy with the potential for a lack of ef-ficacy, increased costs, and adverse events.86,87 Type 1 anaphylactic reac-tions to antimicrobials usually occur 3060 minutes after administration. In patients receiving penicillins, this reaction is a life-threatening emer-gency that precludes subsequent use of penicillins.88 Cephalosporins and carbapenems can safely be used in patients with an allergic reaction to penicillins that is not an IgE-mediated reaction (e.g., anaphylaxis, urticaria, bronchospasm) or exfo-liative dermatitis (Stevens-Johnson syndrome, toxic epidermal necroly-sis), a life-threatening hypersensitiv-

ity reaction that can be caused by b-lactam antimicrobials and other medications.88,89 Patients should be carefully questioned about their history of antimicrobial allergies to determine whether a true allergy exists before selection of agents for prophylaxis. Patients with allergies to cephalosporins, penicillins, or both have been excluded from many clini-cal trials. Alternatives to b-lactam antimicrobials are provided in Table 2 based mainly on the antimicrobial activity profiles against predominant procedure-specific organisms and available clinical data.

Drug administrationThe preferred route of admin-

istration varies with the type of procedure, but for a majority of pro-cedures, i.v. administration is ideal because it produces rapid, reliable, and predictable serum and tissue concentrations.

Timing of initial dose. Successful prophylaxis requires the delivery of the antimicrobial to the operative site before contamination occurs. Thus, the antimicrobial agent should be administered at such a time to pro-vide serum and tissue concentrations exceeding the minimum inhibitory concentration (MIC) for the prob-able organisms associated with the procedure, at the time of incision, and for the duration of the procedure.41,90 In 1985, DiPiro et al.91 demonstrated that higher serum and tissue cepha-losporin concentrations at the time of surgical incision and at the end of the procedure were achieved when the drugs were given intravenously at the time of anesthesia induction compared with administration in the operating room. The average interval between antimicrobial administra-tion and incision was 1722 minutes91 (Dellinger EP, personal communica-tion, 2011 May).

A prospective evaluation of 1708 surgical patients receiving antimicro-bial prophylaxis found that preop-erative administration of antimicro-

bials within 2 hours before surgical incision decreased the risk of SSI to 0.59%, compared with 3.8% for early administration (224 hours before surgical incision) and 3.3% for any postoperative administration (any time after incision).92 In a study of 2048 patients undergoing coronary bypass graft or valve replacement surgery receiving vancomycin pro-phylaxis, the rate of SSI was lowest in those patients in whom an infusion was started 1660 minutes before surgical incision.93 This time interval (1660 minutes before incision) was compared with four others, and the rates of SSIs were significantly lower when compared with infusions given 015 minutes before surgical inci-sion (p < 0.01) and 121180 minutes before incision (p = 0.037). The risk of infection was higher in patients receiving infusions 61120 minutes before incision (odds ratio [OR], 2.3; 95% confidence interval [CI], 0.985.61) and for patients whose infusions were started more than 180 minutes before surgical incision (OR, 2.1; 95% CI, 0.825.62).93

In a large, prospective, multi-center study from the Trial to Reduce Antimicrobial Prophylaxis Errors (TRAPE) study group, the timing, duration, and intraoperative redosing of antimicrobial prophylaxis and risk of SSI were evaluated in 4472 patients undergoing cardiac surgery, hyster-ectomy, or hip or knee arthroplasty.94 The majority of patients (90%) re-ceived antimicrobial prophylaxis per the SCIP guidelines.41 Patients were assigned to one of four groups for analysis. Group 1 (n = 1844) received a cephalosporin (or other antimicro-bial with a short infusion time) ad-ministered within 30 minutes before incision or vancomycin or a fluoro-quinolone within one hour before incision. Group 2 (n = 1796) received a cephalosporin 3160 minutes be-fore incision or vancomycin 61120 minutes before incision. Group 3 (n = 644) was given antimicrobials earlier than recommended, and group



4 (n = 188) received their initial an-timicrobial doses after incision. The infection risk was lowest in group 1 (2.1%), followed by group 2 (2.4%) and group 3 (2.8%). The risk of infec-tion was highest in group 4 (5.3%, p = 0.02 compared with group 1). When cephalosporins and other an-timicrobials with short infusion times were analyzed separately (n = 3656), the infection rate with antimicrobi-als administered within 30 minutes before incision was 1.6% compared with 2.4% when antimicrobials were administered 3160 minutes before incision (p = 0.13).

In a multicenter Dutch study of 1922 patients undergoing total hip arthroplasty, the lowest SSI rate was seen in patients who received the antimicrobial during the 30 minutes before incision.95 The highest risk for infection was found in patients who received prophylaxis after the incision.

It seems intuitive that the entire antimicrobial dose should be infused before a tourniquet is inflated or before any other procedure that re-stricts blood flow to the surgical site is initiated; however, a study of total knee arthroplasties compared cefu-roxime given 1030 minutes before tourniquet inflation with cefuroxime given 10 minutes before tourniquet deflation and found no significant difference in SSI rates between the two groups.96

Overall, administration of the first dose of antimicrobial beginning within 60 minutes before surgical in-cision is recommended.41,94,97 Admin-istration of vancomycin and fluoro-quinolones should begin within 120 minutes before surgical incision be-cause of the prolonged infusion times required for these drugs. Because these drugs have long half-lives, this early administration should not com-promise serum levels of these agents during most surgical procedures. Although the recent data summarized above suggest lower infection risk with antimicrobial administration

beginning within 30 minutes before surgical incision, these data are not sufficiently robust to recommend narrowing the optimal window to begin infusion to 130 minutes before surgical incision. However, these data do suggest that antimicrobials can be administered too close to the time of incision. Although a few articles have suggested increased infection risk with administration too close to the time of incision,93,96,97 the data presented are not convincing. In fact, all of these articles confirm the in-creased rate of SSI for antimicrobials given earlier than 60 minutes before incision. In one article, the infection rate for patients given an antimicro-bial within 15 minutes of incision was lower than when antimicrobials were given 1530 minutes before incision.97 In another article, small numbers of patients were reported, and an asser-tion of high infection rates for infu-sion within 15 minutes of incision was made, but no numeric data or p values were provided.98 In a third article, only 15 of over 2000 patients received antimicrobials within 15 minutes be-fore incision.93 Earlier studies found that giving antimicrobials within 20 minutes of incision and as close as 7 minutes before incision resulted in therapeutic levels in tissue at the time of incision.41,90,91,94,97,98

Dosing. To ensure that adequate serum and tissue concentrations of antimicrobial agents for prophylaxis of SSIs are achieved, antimicrobial-specific pharmacokinetic and phar-macodynamic properties and patient factors must be considered when selecting a dose. One of the earliest controlled studies of antimicrobial prophylaxis in cardiac surgery found a lower rate of infection in patients with detectable concentrations of the drug in serum at the end of surgery compared with patients in whom the drug was undetectable.99 In another study, higher levels of antimicrobial in atrial tissue at the time of starting the pump for open-heart surgery were associated with fewer infections

than were lower antimicrobial con-centrations.100 In patients undergo-ing colectomy, infection levels were inversely related to the serum gen-tamicin concentration at the time of surgical closure.17 In general, it seems advisable to administer prophylactic agents in a manner that will ensure adequate levels of drug in serum and tissue for the interval during which the surgical

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