Pharmacokinetics–pharmacodynamics issues relevant for the ......REVIEW Open Access Pharmacokinetics–pharmacodynamics issues relevant for the clinical use of beta-lactam antibiotics

REVIEW Open Access

Pharmacokinetics–pharmacodynamicsissues relevant for the clinical use of beta-lactam antibiotics in critically ill patientsRui Pedro Veiga1,2,3* and José-Artur Paiva1,2,3

Abstract

Antimicrobials are among the most important and commonly prescribed drugs in the management of criticallyill patients and beta-lactams are the most common antibiotic class used. Critically ill patient’s pathophysiologicalfactors lead to altered pharmacokinetics and pharmacodynamics of beta-lactams.A comprehensive bibliographic search in PubMed database of all English language articles published from January2000 to December 2017 was performed, allowing the selection of articles addressing the pharmacokinetics orpharmacodynamics of beta-lactam antibiotics in critically ill patients.In critically ill patients, several factors may increase volume of distribution and enhance renal clearance, inducinghigh intra- and inter-patient variability in beta-lactam concentration and promoting the risk of antibiotic underdosing.The duration of infusion of beta-lactams has been shown to influence the fT >minimal inhibitory concentration and animproved beta-lactam pharmacodynamics profile may be obtained by longer exposure with more frequent dosing,extended infusions, or continuous infusions.The use of extracorporeal support techniques in the critically ill may further contribute to this problem and werecommend not reducing standard antibiotic dosage since no drug accumulation was found in the availableliterature and to maintain continuous or prolonged infusion, especially for the treatment of infections caused bymultidrug-resistant bacteria.Prediction of outcome based on concentrations in plasma results in overestimation of antimicrobial activity at thesite of infection, namely in cerebrospinal fluid and the lung. Therefore, although no studies have assessed clinicaloutcome, we recommend using higher than standard dosing, preferably with continuous or prolonged infusions,especially when treating less susceptible bacterial strains at these sites, as the pharmacodynamics profile mayimprove with no apparent increase in toxicity.A therapeutic drug monitoring-guided approach could be particularly useful in critically ill patients in whomachieving target concentrations is more difficult, such as obese patients, immunocompromised patients, thoseinfected by highly resistant bacterial strains, patients with augmented renal clearance, and those undergoingextracorporeal support techniques.

Keywords: Critical care or intensive care or critically ill, Sepsis or septic shock, Antibiotics, Pharmacokinetics,Pharmacodynamics

* Correspondence: [email protected] Hospitalar São João, EPE – Intensive Care Department, Porto,Portugal2Faculty of Medicine – University of Porto, Porto, PortugalFull list of author information is available at the end of the article

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Veiga and Paiva Critical Care (2018) 22:233 https://doi.org/10.1186/s13054-018-2155-1

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BackgroundAntimicrobials are among the most important and com-monly prescribed drugs in the management of criticallyill patients and beta-lactams are the most common anti-biotic class used because of their broad spectrum of ac-tivity and high tolerability [1, 2].Early and appropriate antibiotic administration im-

proves clinical outcome of septic patients [3–7]. In thepresence of septic shock, besides conflicting results [8,9], each hour delay is associated with a measurable in-crease in mortality and other negative endpoints (e.g.,length of stay in ICU, acute kidney injury, acute lung in-jury, and global organ injury assessed by theSepsis-Related Organ Assessment score) [10, 11].Choosing the appropriate antimicrobial for the bacter-

ial activity spectrum is crucial but the correct dosageregimen (both dose and frequency) is, at least, of thesame importance for successful clinical cure and micro-biological eradication [11].Unlike organotropic drugs, where it is easy to titrate dose

to achieve a clinical response, antibiotics may take 24–72 hto present signs of resolution of infection, making it diffi-cult to determine the most appropriate dosage [1, 2].We conducted a comprehensive bibliographic search

in the PubMed database of all English language articlespublished from January 2000 to December 2017, usingthe following keywords: critical care or intensive care orcritically ill and sepsis or septic shock and antibioticsand pharmacokinetics or pharmacodynamics. Articlesnot addressing beta-lactam pharmacokinetics (PK) orpharmacodynamics (PD) in critically ill patients were ex-cluded. A small number of articles derived from refer-ences in the articles selected were also reviewed. In theend, 214 studies were included in our review (Fig. 1).

Beta-lactam PD characteristicsKnowledge of the antimicrobial PD characteristics (in-hibition of growth, rate and extent of bactericidal action,and post-antibiotic effect (PAE)) provides a more ra-tional basis for determination of optimal dosing regi-mens in terms of the dose and the dosing interval.The antimicrobial activity of drugs is usually assessed

by determination of the minimum inhibitory concentra-tion (MIC) and the minimum bactericidal concentration(MBC) of the drug under specific conditions in vitro.These in vitro conditions are very different from thoseexpected at the site of infection, where the milieu is fre-quently acidic and anaerobic, and tissue protein maybind a variable amount of the drug. Additionally, theseparameters do not provide information on the timecourse of the antimicrobial effect—the fluctuating levelsthat are present in a patient treated with the drug—andare measured against a standard bacterial inoculum(about 10 colony-forming units (CFU) per millilitre [5])

that does not necessarily correspond to bacterial dens-ities at site of infection (10 CFU per gram of tissue orpus [8–10]). For bactericidal drugs, the MBC is generallynot more than fourfold higher than the MIC. The size ofthe residual bacterial population at the end of each dos-ing interval, and ultimately the efficacy of the antimicro-bial regimen, depends on the interplay of a variety ofbacterial, drug, and host factors that include the size ofthe initial bacterial population, the potency (MIC andMBC) and PK characteristics of the antimicrobial agent,the rate and extent of any bactericidal effect, the pres-ence of a post-antibiotic effect (PAE), the rate ofre-growth of persistent organisms, and the state of hostdefences [13].Three PD indices describe optimal killing associated

with antibiotics: fT >MIC, which is the amount of timethat the unbound drug concentration remains above theMIC of the infecting organism; Cmax/MIC, which is theratio between the maximum concentration of the drugand the MIC of the infecting organism; and AUC0–24/MIC, which is the ratio between total area under theconcentration–time curve (AUC) over 24 h and the MICof the infecting organism.Beta-lactams are time-dependent antimicrobials whose

efficacy is mainly related to fT >MIC [1, 2, 12–14].

299 Articles Reviewed

209 Articles Selected

3 articles selected from references of

these 211

212 Articles Selected

90 Articles Excluded: 45 addressing PK-PD issues of other classes of antibiotics;

1 addressing lesion consecutive to adverse event

11 not evaluating PK-PD issues;

3 addressing study protocols;

1 addressing prophylactic therapy;

1 addressing empirical therapy

19 addressing non-critically ill patients;

4 corresponding letters;

1 book chapter

3 in vitro studies;

1 addressing PK-PD issues of non-antibiotics.

Fig. 1 Articles reviewed, included, and excluded

Veiga and Paiva Critical Care (2018) 22:233 Page 2 of 34

Increasing drug concentrations much above the MBCdoes not enhance bacterial killing and the bactericidalaction of these drugs is relatively slow. When druglevels at the site of infection fall below the MIC, therelatively large residual population can resume growthquickly because most beta-lactams either have no oronly a short PAE [12]. McKinnon et al. compared thePD of cefepime and ceftazidime and observed that pa-tients with fT >MIC of 100% had significantly greaterrates of clinical cure and bacteriological eradicationthan patients with fT >MIC of < 100% [15].It is suggested that 50% fT >MIC of the dosage inter-

val is needed to ensure standard efficacy with these anti-microbials, whereas 100% fT >MIC of the dosageinterval should be ensured for optimal exposure in im-munocompromised patients. A further improvement inefficacy is observed when antibiotic concentrations arefour to five times greater than MIC [2, 12, 13]. The per-centage of time above MIC that correlates with efficacyvaries among different beta-lactam groups, being greaterfor cephalosporins and aztreonam than for penicillins,and greater for penicillins than for carbapenems. Also,variations occur among different bacterial species, beingless for staphylococci, for which beta-lactams have aPAE, than for streptococci and Gram-negative bacilli, forwhich beta-lactams do not have a PAE [2, 13].

Beta-lactam PK issues in the critically illDiscovered antibiotics are evaluated in vitro and testedin animals, initially for toxicity and subsequently for effi-cacy. The antibiotic dose and frequency are based onthese in vitro or animal in vivo PK/PD studies. Thesedosing regimens are then tested on healthy human vol-unteers for tolerability, with clinical efficacy studiesundertaken in non-critically ill patients. After the launchof the drug onto the general market, the same dosingregimen is used in critically ill patients; however, this islikely to lead to suboptimal outcomes in the ICU [5], es-pecially with more resistant bacterial strains [16] and inthe immunocompromised population [17].Beta-lactams are hydrophilic drugs and so their vol-

ume of distribution (Vd) is low and similar to that ofextracellular water. Variations in the extracellular fluidcontent and/or in renal or liver function may be consid-ered the most relevant and frequent pathophysiologicalmechanisms possibly affecting drug disposition in critic-ally ill patients. Other factors may contribute to alteredantibiotic concentrations: an interesting case-report byTaccone et al. [18] related the case of an obese septic pa-tient with Pseudomonas aeruginosa pneumonia treatedwith meropenem. The PD target (t > 4 × MIC > 40% ofthe dosing interval) was only achievable by dosing 3 gq6h at 3 h extended infusion and was associated withclinical improvement.

Compared with healthy volunteers and non-critically illpatients, in critically ill patients capillary leakage andedema, fluid therapy, pleural effusion, ascites, indwellingpost-surgical drainage, and hypoalbuminemia may in-crease Vd and cause antibiotic dilution in plasma andextracellular fluids. Some pathophysiological factors mayalso enhance (trauma, burns, the hyperdynamic conditionof the early phase of sepsis, the use of hemodynamicallyactive drugs) or reduce (renal failure, muscular wastage,bedridden patients) renal clearance and consequently mayalter plasma and extracellular antibiotic concentrations(with implications on time over MIC), induce high intra-and inter-patient variability, and promote the risk of anti-biotic underdosing [1, 2, 12, 14, 19–35]. Extracorporealsupport techniques also contribute to antibiotic concen-tration variability [36].PK studies on ICU septic patients reported, overall, in-

creased Vd with significant daily concentration fluctua-tions between and within patients [5, 36–41]. Clearanceof drugs is also affected and usually related to creatinineclearance [1, 42–44]. A single-center study of 17 ICUpatients with ventilator-associated pneumonia (VAP) de-scribed the PK profile of ertapenem and concluded that,because of its highly protein-bound profile, hypoalbu-minemia resulted in a higher protein-unbound fractionwith consequences for drug distribution and elimination[38]. Ulldemolins et al. [39] found the same while study-ing the PK profile of flucloxacillin. Ramon-Lopez et al.[45] described high PK variations (between and withinpatients) for meropenem in 12 burn ICU patients thatwere mostly related to age, body weight, and serum al-bumin. Carlier et al. [37] investigated the adequacy ofpiperacilin/tazobactam dosing and its trough variabilityduring an entire 7-day antibiotic course in 11 ICUpatients with pneumonia and normal renal function. Sixof them failed to achieve the PK/PD target of 100% fT >MIC at least once during the treatment course and con-siderable antibiotic concentration variability was foundwithin and between patients. The DALI study, a largemulticenter prospective study evaluated 248 ICU pa-tients treated for infection with beta-lactams and foundlarge variations on beta-lactam blood concentrations.The achievement of the PK/PD targets was highly incon-sistent, with one fifth of the patients not achieving theirmost conservative PK/PD target of 50% fT >MIC andbetter outcomes were described with higher drug expos-ure, at least for less severely ill patients [5].Septic patients with acute renal failure may have sub-

optimal antibiotic concentrations in the first days oftherapy when the recommended dosing adjustment forrenal failure is used [46]. Taconne et al. [40] studied thePK profiles of four beta-lactams (ceftazidime, cefepime,piperacilin/tazobactam, and meropenem) over the first24 h of treatment in 80 septic ICU patients. They


concluded that, besides high intra- and inter-patient PKvariability, standard first doses of broad-spectrumβ-lactams provided inadequate levels to achieve targetserum concentrations for extended periods of time.Augmented renal clearance has probably more impact

than altered Vd on the PK of beta-lactams [25, 27, 47–54].Roberts et al. [23] described the PK of cefazolin in plasmaand interstitial fluid of subcutaneous tissue in post-traumacritically ill patients and demonstrated that increasing cre-atinine clearance (ClCr) or decreasing serum albuminconcentrations will reduce the likelihood of achieving op-timal cefazolin exposure in subcutaneous interstitial tis-sue. In the presence of augmented renal clearance (ClCr> 130 mL/min), a much higher dose of cefazolin is re-quired to obtain similar relative drug exposures [23]. Conilet al. [43] found that higher ClCr values (> 50 mL/min)did not provide trough concentrations of piperacilin (4 gthree times a day) sufficient enough to attain the MIC formany pathogens in many of the patients studied.Hypoalbuminemia has also been associated with altered

PK. Wong et al. [55] described a linear correlation be-tween the percentage protein binding of flucloxacillin andthe plasma albumin concentration, though this was nottrue for ceftriaxone. Also, plasma albumin concentrationsand in vitro binding data from healthy volunteers shouldnot be used to predict unbound concentrations of ceftri-axone in ICU patients [56].

Use of extracorporeal support techniques incritical careAcute kidney injury (AKI) occurs in 50 to 65% ofcritically ill patients and in approximately two-thirdsof patients within the first 24 h after admission tothe intensive care unit (ICU) [57]. Critically ill pa-tients are usually supported with one of the forms ofcontinuous renal replacement therapy (CRRT)—con-tinuous venous-venous hemofiltration, hemodiafiltra-tion, hemodialysis (CVVHF, CVVHDF, CVVHD,respectively)—or with sustained low-efficiency dialysis(SLED). Molecules are transported across the filtermembrane by the mechanism of convection (drivenby the pressure gradient—CVVHF), diffusion (drivenby the concentration gradient—CVVHD, SLED), orboth (CVVHDF).Employing CRRT complicates antibiotic dosing to a

significantly higher extent than standard hemodialysisdue to the high number of variables, including Vd, flowof the dialysis fluid, replacement fluid infusion site (pre-or post-dilution mode), type and surface of the usedmembrane, and the difference between delivered andprescribed RRT dose.Vd in AKI may be significantly different from published

population estimates derived from healthy subjects.Besides the decreased plasma protein concentrations in

acutely ill patients, uremic solutes, such as hippurate andindoxyl sulfate, alter drug binding to albumin in chronicrenal failure and might do so in acute renal failure, al-though this has not been tested. The free fraction of manydrugs is increased in renal failure, even though the Vd fortotal drug may increase due to movement of unbounddrug into interstitial or total body water [57–59].Overall, a tendency for antibiotic underdosing in critic-

ally ill patients on CRRT or SLED likely exists. The modeand dose of CRRT vary quite widely from center to centerand from report to report, making it very difficult to cre-ate generally applicable beta-lactam dosing guidelines forcritically ill patients under CRRT. Additionally, antibioticconcentrations may vary depending on the degree of ex-traction and residual renal function, which is variable, dif-ficult to assess, and rarely considered despite its relevantcontribution to antibiotic clearance in patients undergoingCRRT (Tables 1 and 2) [60–96].Globally, we recommend not reducing standard anti-

biotic dosage since no drug accumulation was found inthe available literature and to maintain continuous or pro-longed infusion in critically ill patients on CRRT, SLED, orEDD, especially for the treatment of multidrug-resistantbacteria. Although usually not available in clinical rou-tines, a therapeutic drug monitoring (TDM)-guided strat-egy has potential benefit to ensure appropriate antibiotictherapeutic targets.Extracorporeal membrane oxygenation (ECMO) has

become an essential tool for severe cardiorespiratoryfailure in critically ill patients. It is thought to introduceadditional confounding factors to the already altered PKproperties of beta-lactams in this subset of patients.Sequestration of antibiotics in the ECMO circuit and theassociated systemic inflammation can further increasethe antibiotic Vd and reduce clearance [74, 97–99].However, very few in vivo studies have been performedin this subset of patients (Table 3). Globally, they showno significant statistical variation in Vd and clearance,but while probability of target attainment (PTA) withstandard ICU dosage regimens was achieved when treat-ing for highly susceptible Gram-negative bacteria, anti-biotic concentrations were below those desired to treatmore resistant strains.

Longer exposure regimens: continuous infusion,extended infusion, or reduced-interval dosingThe duration of infusion of beta-lactams has been shownto influence their fT >MIC. Improved PD profiles ofbeta-lactams may be obtained by longer exposure withmore frequent dosing, extended infusions, or continuousinfusions. Several studies reported PD benefits for targetattainment of extended and continuous infusions,especially considering highly resistant bacterial strains,even using smaller daily doses [1, 2, 36, 41, 103–143].


Table

1PK/PDstud

iesof

beta-lactam

sin

patientsun

dergoing

CRRT

Stud

yEndp

oints

Antibiotic

Designandtype

ofCRR

TResults

Con

clusions

Fish

etal.[67]

Tomorefully

characterizePK

disposition

ofim

ipen

emin

critically

illadultpatientsdu

ringcurren

tlyused

CVV

Hor

CVV

HDFregimen

s

Imipen

em-cilastatin

Prospe

ctiveop

en-labe

lstudy

ofim

ipen

em-cilastatin

administeredas

thecombinatio

nprod

uctin

afixed

1:1ratio

Adu

ltICUpatientswith

CVV

H(n

=6

patients)or

CVV

HDF(n

=6patients)

Imipen

emadministeredat

0.5g

every8to

12h(totaldaily

dosesof

1to

1.5g/day)

byintraven

ous

infusion

over

30min

Pre-

andpo

st-m

embraneplasma

andcorrespo

ndingultrafiltrate

ordialysatesamples

werecollected

at1,2,4,and8or

12h(dep

ending

ondo

sing

interval)aftercompletionof

thedrug

infusion

Patientson

CVV

HDFhadsign

ificantly

high

erCLs

comparedto

patientson

CVV

H(P

=0.01),bu

tthisdifference

was

notsign

ificant

whe

nno

rmalized

fortotalb

odyweigh

t(P

=0.477)

Theob

served

t1/2

was

overallsim

ilar

betw

eenbo

thpatient

grou

ps(P

=0.860)

Nosign

ificant

differzen

ceswere

foun

din

Vd,S,and

Sa,or

ultrafiltratio

nrates

MeanCmax,C

min,and

AUC0–24

values

inpatientsreceiving0.5gbid

durin

gCVV

Hversus

CVV

HDFwere

17.5g/mLvs

14.1g/mL,1.1g/mLvs

1.0g/mL,and129.5g·h/mLvs

110.3g·h/mL,respectively,andin

patientsreceiving0.5gtid

they

were

18.5g/mLvs

17.1g/mL,1.9g/mLvs

1.1g/mL,and183.3g·h/mLvs

140.6g·h/mL,respectively

Doses

of0.5gbidand0.5gtid

gene

rally

provided

T>MIC

ofat

least

40to

50%and50

to60%,respectively

(MICsof

<2g/mL)Doses

of0.5g

every6h(2.0g/day)weremod

eled

basedon

thePK

parametersob

served

inthisstud

yandtheT>MIC

calculated:at2.0g/day,organism

swith

aMIC

of<4g/mLhadaT>MIC

ofatleast50

to80%.And

fortho

sewith

MIC

<8g/mL,T>MIC

rang

edfro

m34

to62%

CVV

HandCVV

HDFcontrib

uteto

imipen

emclearanceto

agreater

degree

than

previouslyrepo

rted

.Im

ipen

emdo

sesof

1.0g/dayappe

arto

achieveconcen

trations

adeq

uate

totreatmostcommon

Gram-

negativepathog

ens(MICup

to2g/mL)

butdo

sesof

2.0g/dayor

moremay

berequ

iredto

adequatelytreatand

preventresistanceinpathog

enswith

high

erMICs(M

IC>4to

8g/mL)

Malon

eet

al.

[68]

Tomorefully

characterizethe

PKdisposition

ofcefepimein

critically

illadultICUpatientsdu

ring

CVV

Hor

CVV

HDF

Cefep

ime

Prospe

ctive,ob

servationalstudy

12adultICUpatientsreceivingCRR

Tforsevere

renalfailure

(5patientson

CVV

H,7

patientson

CVV

HDF)

Cefep

imeregimen

sinclud

edeither

1gor

2gdo

sesadministered

intraven

ouslyevery12

or24

h(total

daily

dosesof

1to

4g/day)

Samplingwas

perfo

rmed

assoon

aspo

ssibleafterinitiationof

theCRR

Tanddrug

therapy.Pre-

andpo

st-

mem

braneveno

usbloo

dsamples

wereob

tained

1,2,4,and8hafter

thecompletionof

thedrug

infusion

andjustbe

fore

administrationof

the

next

dose

Drugclearancedu

ringCRR

T(CL

CRR

T)and%CLS

weresign

ificantly

high

er(P

=0.002and0.018,

respectively),and

t1/2

was

sign

ificantlylower

(P=0.005)

amon

gpatientsreceivingCVV

HDFthan

inpatientsreceivingCVV

H.

ThemeancefepimeSdu

ringCVV

HandSa

durin

gCVV

HDFwere

estim

ated

at0.86

±0.04

and0.78

±0.10,respe

ctively,indicatin

gthat

cefepimeisextensivelycleared

across

theCRR

Tmem

brane

App

roximately40

and59%

ofcefepimeCLs

was

attributed

tomem

braneclearancedu

ringCVV

HandCVV

HDF,respectively,indicatin

gthat

theclearanceof

cefepimewas

Itappe

arsthat

CVV

HDFismore

efficient

than

CVV

Hin

elim

inating

cefepime.How

ever,the

presen

tstud

yinclud

edtoofew

subjectsand

toomuchvariabilitywas

observed

with

inthedata

tode

mon

strate

this

conclusively.

Cefep

imeregimen

sof

0.25

to1.0g/

dayas

recommen

dedby

the

manufacturerforanuricpatientsor

thosereceivingconven

tional

hemod

ialysiswou

ldlikelybe

subthe

rape

uticagainstallb

utthe

mosthigh

lysuscep

tiblepathog

ens

whe

nadministeredto

patients

receivingCRR

TTheauthorsrecommen

dcefepime

dosesof

2gdaily

unde

rmost


Table

1PK/PDstud

iesof

beta-lactam

sin

patientsun

dergoing

CRRT(Con

tinued)

Stud

yEndp

oints

Antibiotic

Designandtype

ofCRR

TResults

Con

clusions

substantially

enhanced

durin

gbo

thCRR

Ttechniqu

esValues

forcefepimeVd

werealso

statisticallydifferent

(P=0.03)

betw

eenCVV

HandCVV

HDFgrou

ps,

butchange

sin

Vdwereon

lyweakly

correlated

with

change

sin

t1/2

(Spe

arman’srank

correlation

coefficient

of0.641;P=0.133)

Allpathog

ensisolated

from

stud

ypatientshadcefepimeMICsof

<4g/mL,anddo

sesas

low

as1g/day

wou

ldpred

ictablyprovideadeq

uate

treatm

entdu

ringeither

CVV

Hor

CVV

HDF

Cefep

imedo

sesof

2g/daywou

ldbe

expe

cted

toachievefavorable

concen

trations

inserum

against

suscep

tiblepathog

ens(M

IC<8

g/mL)

with

T>MIC

greaterthan

50%.C

efep

ime(2

g/day)du

ring

either

CVV

Hor

CVV

HDFwou

ldalso

bepred

ictedto

achievefavorable

T>MIC

>80%

againstpathog

ens

with

interm

ediate

suscep

tibility

(MIC

<16

g/mL)

circum

stancesin

critically

illpatients

receivingCR

RT.H

owever,con

sidering

moreresistant

strains,do

sesof

4g/dayshou

ldbe

considered

for

empiricaltherapyinlife-threatening

nosocomialinfectio

ns,w

hileaw

aitin

gresults

ofcultu

reandsusceptib

ility

testing

Muelleret

al.

[69]

Tode

term

inethePK

ofpipe

racillin-

tazobactam

incritically

illpatients

with

acuteanuricrenalfailure

treatedby

CVV

H

Pipe

racilin-tazob

actam

Prospe

ctive,ob

servationalstudy

8adultICUpatientson

CVV

HD

Doses

anddo

sing

sche

duleswere

chosen

empiricallyby

theattend

ing

physicians

andwereadministered

intraven

ouslyover

15min

Pre-dialyzer

bloo

dsamples

and

dialyzer-outletdialysatesamples

weretakenbe

fore

drug

administration,

at10

and30

min

afterinfusion

,and

at1,2,4,6,8,12,

20,22,and24

hafterinfusion

CVV

HDclearanceof

pipe

racillinwas

37%

(med

ian,

with

arang

eof

13to

100%

)andtheCVV

HDclearanceof

tazobactam

was

38%

(med

ian,

with

arang

eof

32to

92%)of

CLtotal

Vdwas

0.31

±0.07

and0.24

±0.09

forpipe

racilin

andtazobactam

,respectively

t1/2

was

4.3±1.2and5.6±1.3for

pipe

racilin

andtazobactam

,respectively

Simulations

of4gof

pipe

racillinand

0.5gof

tazobactam

administered

every12

hand2gof

pipe

racillin

and0.25

gof

tazobactam

administeredevery8hresultedin

times

aboveMIC

of>50%

for

pipe

racillinwith

suscep

tible(M

ICof

pipe

racillin16

mg/liter;tim

eabove

MIC,48to

100%

)andinterm

ediate

suscep

tible(M

IC32

mg/liter;tim

eaboveMIC,17to

100%

)pathog

ens

insevenof

eigh

tpatients

Arelevant

contrib

utionof

CVV

HDto

theoverallelim

inationof

both

drug

shasto

betakeninto

accoun

tTheestim

ated

Vdvalues

aregreater

than

thoseof

healthysubjectsand

t1/2

ofbo

thdrug

swerefourfold

greaterthan

thoseof

healthy

subjectsandtw

ofoldgreaterthan

thosewith

acreatin

ineclearance<

20mL/min/1.73m

2

Patientswith

residu

alrenalfun

ction

andpatientsthat

receiveCRR

Twith

high

erdialysateflow

ratesor

high

eradditio

nalh

emofiltrate

flow

rates

might

have

high

erCLof

pipe

racillin-

tazobactam

,resultin

gin

high

erdo

sage

need

s


Table

1PK/PDstud

iesof

beta-lactam

sin

patientsun

dergoing

CRRT(Con

tinued)

Stud

yEndp

oints

Antibiotic

Designandtype

ofCRR

TResults

Con

clusions

Robe

rtset

al.

[70]

Toassess

thevariabilityof

antib

iotic

trou

ghconcen

trations,the

influen

ceof

effluen

tflow

rateson

such

concen

trations,and

theincide

nceof

subo

ptim

alantib

iotic

dosage

Merop

enem

and

pipe

racilin-tazob

actam

Prospe

ctive,ob

servational,

multicen

terstud

y,cond

uctedwith

inthemulticen

terRENALstud

y.It

assessed

theeffect

ofpo

st-dilutio

nal

high

erintensity

(40mL/kg/h

effluen

trate)or

lower

intensity

(25mL/kg/h

effluen

trate)CRR

T.Patientswere

rand

omized

toreceiveeither

high

eror

lower

intensity

effluen

tflow

rate

24adultICUpatientswith

AKI

onCVV

H.17patientswereon

merop

enem

and7patientson

pipe

racilin-tazob

actam

Antibiotic

dosing

was

atthe

discretio

nof

thetreatin

gph

ysician:

merop

enem

0.5gevery12

hto

1g

every8h;pipe

racilin

4gevery12

hto

4gevery6h

Bloo

dsamples

wereob

tained

onmorethan

oneoccasion

ondifferent

days

andbe

fore

administrationof

theantib

iotic

tode

term

inethe

trou

ghconcen

tration

Therewas

markedvariabilityin

trou

ghconcen

trations

forall

antib

iotics:6.7-fold

formerop

enem

;3.8-fold

forpipe

racillin;

10.5-fo

ldfor

tazobactam

Whe

ninvestigatingtrou

ghconcen

trationvariabilityaccordingto

effluen

tflow

rate,n

ostatistically

sign

ificant

differences

werefoun

dusingun

ivariate

analysis

Merop

enem

trou

ghconcen

trations

were10.1±8.7and15.0±6.4for

low

andhigh

effluen

tflow

rates,

respectively

Pipe

racilin

trou

ghconcen

trations

were83.6±63.8and204.0±105.0

forlow

andhigh

effluen

tflow

rates,

respectively

100%

T>MIC

was

achieved

with

merop

enem

(forMIC

2mg/L)

and

pipe

racilin-tazob

actam

(forMIC

16mg/L)

76%

T>MIC

was

achieved

for

merop

enem

(forMIC

8mg/L)

86%

T>MIC

was

achieved

for

pipe

racilin-tazob

actam

(forMIC

64mg/L)

Itappe

arsthat

CRR

Teffluen

tflow

ratescann

otbe

used

inde

pend

ently

togu

idedo

seadjustmen

tTrou

ghconcen

trations

failedto

achievethehigh

ertherapeutic

target

in24%

ofpatientsreceiving

merop

enem

and14%

ofpatients

receivingpipe

racillin,

which

isof

concern

Dose-adjustingto

achieveatarget

concen

trationthat

exceed

sthe

approp

riate

MIC

butisless

than

potentially

toxicconcen

trations

seem

sde

sirablebu

tcann

otbe

reliablyachieved

with

empirical

dosing

Banyaiet

al.[71]

Tostud

ythePK

ofcefpiro

mein

critically

illpatientswith

acute

kidn

eyfailure

treatedby

CVV

Hand

tode

velopan

optim

aldo

sing

regimen

inpatientswith

CVV

H

Cefpirome

Prospe

ctive,ob

servationalstudy

8adultICUanuricpatientswith

acutekidn

eyfailure

onCVV

HAllpatientsreceived

ado

sage

of2g

cefpiro

meover

ape

riodof

30min,

every8hafterstartin

gthe

hemofiltratio

nBloo

dsamples

werecollected

from

thearterialand

veno

uslineof

the

extracorpo

realcircuitim

med

iatelyat

baselineandat

60,120,180,240,

300,360,and420min

afterthestart

ofthefirstinfusion

.Add

ition

albloo

dsamples

werecollected

immed

iately

before

theen

dand30

min

afterthe

endof

each

infusion

,upto

atotal

stud

ype

riodof

48h

Ultrafiltratio

nsamples

werecollected

from

theou

tletof

theultrafiltrate

compartmen

tof

thehe

mofilter

atcorrespo

ndingtim

es

Cmax14.8±3.2μg

/mL(10.8to

19.7)

Cmin3.1±0.8μg

/mL

Posthe

mofiltratio

nto

pre-

hemofiltratio

nratio

of0.23

±0.10

Totald

rugremovalof

78.0%±8.8%

Elim

inationt1/2

was

2.36

±0.59

h(1.6to

3.2h).The

calculated

Vdwas

118±36

LTotalb

odyclearanceand

hemofiltratio

nclearancewere589.1

±164.5mL/min

and43.3±7.8mL/

min,respe

ctively

Thecalculated

AUCwas

60.4±

16.0mg/L·h

Highe

stlevelsof

cefpiro

mewere

sign

ificantlylower

comparedwith

values

observed

inhe

althy

volunteersandin

patientson

hemod

ialysis

Plasmacefpiro

meconcen

trations

remaine

dabove4μg/mLfor62%

andabove8μg/mLfor25%

ofthe

dosing

interval,respe

ctively

Inpatientsinfected

with

aninterm

ediate

suscep

tible

Pseudo

mon

asaerugino

sa(M

IC90

~8mg/L),n

osufficien

tantim

icrobial

efficacycanbe

expe

cted

Com

parablelow

trou

ghlevelsof

3.1±0.8μg/mLsugg

estado

sage

recommen

datio

nof

2gcefpiro

me

every8h


Table

1PK/PDstud

iesof

beta-lactam

sin

patientsun

dergoing

CRRT(Con

tinued)

Stud

yEndp

oints

Antibiotic

Designandtype

ofCRR

TResults

Con

clusions

Eyleret

al.[72]

Tode

term

inethePK

ofertape

nem

incritically

illadultsreceivingCVV

HD

orCVV

HDF

Ertape

nem

Prospe

ctive,op

en-labe

l,first-dosePK

stud

y8adultICUpatientswith

suspected

orconfirm

edGram-neg

ative

infections

receivingCVV

HD

(4patients)or

CVV

HDF(4

patients)

1gertape

nem

was

administeredas

ahalf-ho

urintraven

ousinfusion

Bloo

dsamples

werecollected

from

theCVV

HDcircuitat

thesampling

port,justbe

fore

thehe

mod

ialysis

filterat

timezero

(baseline),30min

(end

ofinfusion

),and1,2,4,8,12,

18,and

24hafterthestartof

the

ertape

nem

infusion

.Atthesame

timepo

ints,effluent

was

also

collected

from

theeffluen

tpo

rtof

theCVV

HD/F

circuit

CLS,unb

ound

48mL/min

VC,unb

ound

32l

VP,unb

ound

21l

CLdial,un

boun

d36

mL/min

PTA(40%

T>MIC)andfractionof

the

dosage

intervalspen

tabovetheMIC

fordifferent

regimen

swere

ForMIC

of0.5mg/L

500mgq1

2h,1.0and0.999

500mgq2

4h,1.0and0.999

750mgq2

4h,1.0and0.999

1000

mgq2

4h,1.0and0.999

ForMIC

of1mg/L

500mgq1

2h,1.0and0.999

500mgq2

4h,0.99and0.916

750mgq2

4h,1.0and0.999

1000

mgq2

4h,1.0and0.999

ForMIC

of2mg/L

500mgq1

2h,1.0and0.992

500mgq2

4h,0.962

and0.563

750mgq2

4h,0.999

and0.750

1000

mgq2

4h,0.999

and0.917

Theun

boun

dfraction(20to

40%)

was

markedlyincreasedcompared

tothoserepo

rted

forhe

althy

volunteers(5

to15%)

Attheeffluen

trates,ertape

nem

was

clearedto

asubstantiald

egree

Duringthestud

ysamplingpe

riod,

thedo

seof

1gevery24

hprod

uced

unbo

undertape

nem

concen

trations

that

remaine

dabove2μ

g/mLforan

averageof

90%

ofthedo

sing

interval,achieving

thePD

targetsin

alleight

patients

Mon

teCarlo

simulations

revealed

that

99.9%

ofsimulated

subjects

wou

ldachieveun

boun

dertape

nem

concen

trations

above2μ

g/mLforat

least40%

oftheinterval,w

ithconcen

trations

remaining

above

2μg/mLforamed

ianof

92%

(rang

e,33

to100%

)of

thedo

sing

interval

Particularlyin

patientswhe

reorganism

swith

high

MICsare

suspected,

itmay

bene

cessaryto

usedo

ses>500mgq2

4h.

Con

centratio

nsremaine

dabove

2μg/mLforan

interquartile

rang

eof

only50

to67%

ofthedo

sing

interval

Vossen

etal.

[73]

TocharacterizethePK

profile

of1000

mgdo

ripen

emq8

hforcritically

illpatientsreceivingCRR

T

Doripen

emProspe

ctive,op

en-labe

l,ob

servationalstudy

13adultICUpatientsun

derCRR

T(5

onCVV

H,5

onCVV

HD,3

onCVV

HDF)

Allpatientsreceived

1000

mgevery

8hat

a30-m

ininfusion

Bloo

danddialysatesamples

were

draw

nfro

mthearterial(inpu

t),

veno

us(outpu

t),and

effluen

tdialysatepo

rtsof

thedialysis

machine

before

thefirst

administrationof

dorip

enem

andat

0.5,1,2,3.5,7,8,9,16,17,24,24.5,

25,26,27.5,31,32,33,40,41,and

48hfollowingthestartof

thefirst

infusion

Allpatients:AUC0–8(m

g·h/L)

78.58

±10.32;Clto

t(L/h)8.07

±1.77;

Clpre-postfilter(m

L/min)36.06±

14.27;Sc

0.150±0.053;ClSc(m

L/min)5.20

±1.95;Vdtotal59.26

±26.47;t1/2

(h)5.39

±2.84

Patientson

CVV

H(n

=3):A

UC0–8

(mg·h/L)

87.15±8.13;C

ltot(L/h)

6.53

±1.00;C

lpre-postfilter(m

L/min)

63.82±5.83;Sc0.129±0.033;ClSc

(mL/min)6.45

±1.81;Vdtotal

51.05±10.18;t1/2

(h)5.72

±1.96

Patientson

CVV

HD(n

=5):A

UC0–8

(mg·h/liter)77.59±12.31;Clto

t(L/h)

7.48

±1.43;C

lpre-postfilter(m

L/min)

34.03±7.22;Sc0.164±0.067;ClSc

(mL/min)5.63

±2.30;Vdtotal71.01

±34.98;t1/2

(h)6.80

±3.37

Patientson

CVV

HDF(n

=5):A

UC0–8

(mg·h/L)

76.15±4.50;C

ltot(L/h)

9.29

±1.28;C

lpre-postfilter(m

L/min)

26.99±5.34;Sc0.145±0.035;ClSc

(mL/min)4.68

±1.43;Vdtotal50.80

Themeanhe

mofilter

clearancerates

observed

slightlyexceed

edthose

repo

rted

intheliterature

Thesievingcoefficientsob

served

differeddram

aticallyfro

mthose

repo

rted

previously

Theprefilter/postfilter

clearance

values

foun

din

ourtrialare

with

intherang

eof

values

repo

rted

previouslyforim

ipen

emand

merop

enem

Therewas

anun

characteristicallylow

clearanceforCVV

HDFpatients,

which

may

beattributed

tothe

larger

mem

branesize

andhigh

ermem

branekU

Fem

ployed

forthe

CVV

HFandCVV

HDgrou

ps.The

usual

expe

ctationforbe

ta-lactam

antim

icrobialswou

ldbe

quite

the

oppo

site:C

VVHDFclearancevalues

shou

ldbe

high

erthan

CVV

HDor

CVV

Hclearancevalues.H

owever,this

istrue

onlyifthesameflow

rates


Table

1PK/PDstud

iesof

beta-lactam

sin

patientsun

dergoing

CRRT(Con

tinued)

Stud

yEndp

oints

Antibiotic

Designandtype

ofCRR

TResults

Con

clusions

±6.34;t1/2(h)3.87

±0.80

Thesimulations

cond

uctedshow

that

theprop

osed

dose

levelo

f1000

mgevery8hissupe

riorto

lower

dosesforreaching

thede

sired

plasmado

ripen

emconcen

trationof

8mg/L.Alth

ough

meantrou

ghconcen

trations

inalld

osing

regimen

sexceed

ed4mg/Ldu

ring

steady

state,theindividu

alou

tcom

eswerehigh

lyvariable

Atado

seof

500mgevery8h,

only

39.5%

ofthesimulated

patients

show

edtrou

ghconcen

trations

that

wereconstantlyabovethelower

threshold(4

mg/L)

durin

gsteady

state.Atado

seof

1000

mgevery

8h,

plasmaconcen

trations

stillfell

below

8mg/L,bu

tno

tlower

than

4mg/L,for60.5%

ofthesimulated

patients

andmem

branematerialsarechosen

.Ifthe1-gq8

hregimen

isused

,39.5%

ofthepatientswillreacha

trou

ghlevelo

f8mg/Lat

theen

dof

each

dosing

interval.Toattain

sufficien

tdrug

expo

sure

durin

gthe

firstdo

singintervaltheadministratio

nof

aninitial“loadingdo

se”of

20.4mg/

kgof

body

weigh

tissugg

ested

Thebroadtherapeutic

inde

xof

beta-lactam

sfavorshigh

erdo

sing

,providingsafety

marginformore-

effectiveRR

Tmod

alities

Carlieret

al.[74]

Tode

scrib

ethePK

ofcefepimein

septicshockpatientsrequ

iring

CRR

Tandto

investigatewhe

ther

PK/PD

targetsareachieved

with

curren

tdo

sing

strategies

aswellasto

investigatethepo

tentialadvantage

sof

alternativedo

sing

regimen

s

Cefep

ime

Prospe

ctive,ob

servationalstudy


septic

shockandon

CRR

T(CVV

HFor

CVV

HDF)

Patientsreceived

2gq8

hor

q12h

.Thedo

sewas

administeredas

a30-m

inintraven

ousinfusion

Bloo

dsamples

weredraw

non

the

dayof

inclusionandthen

every

second

daydu

ringCRR

Ttreatm

ent

whe

neverpo

ssible.O

neach

samplingday,bloo

dsamples

were

draw

nim

med

iatelybe

fore

antib

iotic

administration(0

h)andthen

at1,2,

and5handat

6or

12h(dep

ending

ontheantib

iotic

regimen

)afterthe

startof

theinfusion

CL(L/h)4.5

Vd(L)40.6

PTAat

different

UFR

consideringa

MIC

of16

mg/L

UFR

1000

mL/h

1gq1

2h100%

T>MIC

64%

and

60%T>MIC

95%

2gq1

2h100%

T>MIC

89%

and

60%T>MIC

99%

1gq8

h100%

T>MIC

95%

and

60%T>MIC

100%

2gq8

h100%

T>MIC

99%

and

60%T>MIC

100%

1gq6

h100%

T>MIC

100%

and

60%T>MIC

100%

UFR

1500

mL/h

1gq1

2h100%

T>MIC

31%

and

60%T>MIC

80%

2gq1

2h100%

T>MIC

82%

and

60%T>MIC

98%

1gq8

h100%

T>MIC

87%

and

60%T>MIC

99%

2gq8

h100%

T>MIC

96%

and

60%T>MIC

100%

1gq6

h100%

T>MIC

97%

and

60%T>MIC

100%

UFR

2000

mL/h

1gq1

2h100%

T>MIC

9%and

Antibiotic

clearancewas

prop

ortio

nal

toUFR,w

ithim

portantvariability

betw

eenpatientsbo

thforclearance

andVd

Ado

seof

2gq8

hor

1gq6

hleads

toop

timaltarget

attainmen

t(100%

T>MIC)whilstminim

izingthe

prob

ability

ofreaching

toxictrou

ghconcen

trations

forpatientstreated

with

ahigh

UFR

(1500–2000

mL/

min).How

ever,the

optim

aldo

sefor

patientstreatedwith

lower

UFRs

(≤1000

mL/h)

whe

naimingforthe

high

target

was

1gq8

h


Table

1PK/PDstud

iesof

beta-lactam

sin

patientsun

dergoing

CRRT(Con

tinued)

Stud

yEndp

oints

Antibiotic

Designandtype

ofCRR

TResults

Con

clusions

60%T>MIC

51%

2gq1

2h100%

T>MIC

73%

and

60%T>MIC

95%

1gq8

h100%

T>MIC

79%

and

60%T>MIC

95%

2gq8

h100%

T>MIC

92%

and

60%T>MIC

100%

1gq6

h100%

T>MIC

93%

and

60%T>MIC

100%

Seyler

etal.[75]

Toevaluate

whe

ther

the

recommen

deddo

sesof

broad-

spectrum

beta

-lactam

sresultin

approp

riate

serum

concen

trations

inICUpatientswith

severe

sepsisand

septicshockreceivingCRR

T

Merop

enem

Pipe

racilin-tazob

actam

Cefep

ime

Ceftazidime

Prospe

ctive,op

en-labe

lstudy


severe

sepsisor

septicshockon

CRR

T(CVV

H,n

=19

orCVV

HDF,n=34)

Merop

enem

1gq1

2h(n

=17)

Pipe

racilin-tazob

actam

4.5gq6

h(n

=16)Cefep

ime2gq1

2h(n

=8)

Ceftazidime2gq1

2h(n

=12)

Each

antib

iotic

dose

was

administeredas

a30-m

ininfusion

Serum

concen

trations

ofthese

antib

ioticswerede

term

ined

from

samples

takenbe

fore

(t=0)

and1,2,

5,and6or

12h(dep

ending

onthe

bea-lactam

regimen

)afterthe

administrationof

each

antib

iotic

Seriesof

measuremen

tswere

separatedinto

thosetakendu

ring

theearly

phase(<

48hfro

mthefirst

dose)of

therapyandthosetaken

later(>

48h)

Merop

enem

Vd(l/kg)0.45

(0.20to

3.03)

Cmax

(μg/mL)

26(15to

67)

Cmin

(μg/mL)

6(2

to11)

AUC(m

g/h/mL)

134(61to

291)

CL(m

L/min/kg)

1.15

(0.54to

3.37)

t1/2

(h)4.39

(2.61to

30.5)

Pipe

racilin-tazob

actam

Vd(l/kg)0.44

(0.22to

1.72)

Cmax

(μg/mL)

138(36to

262)

Cmin

(μg/mL)

60(4

to155)

AUC(m

g/h/mL)

527(62to

1378)

CL(m

L/min/kg)

1.15

(0.27to

6.26)

t1/2

(h)4.16

(1.05to

15.3)

Cefep

ime

Vd(l/kg)0.55

(0.33to

0.94)

Cmax

(μg/mL)

43(28to

83)

Cmin

(μg/mL)

11(3

to22)

AUC(m

g/h/mL)

379(148

to483)

CL(m

L/min/kg)

1.04

(0.43to

2.97)

t1/2

(h)6.17

(3.30to

22.9)

Ceftazidime

Vd(l/kg)0.37

(0.22to

0.84)

Cmax

(μg/mL)

78(54to

118)

Cmin

(μg/mL)

24(5

to46)

AUC(m

g/h/mL)

536(258

to906)

CL(m

L/min/kg)

0.52

(0.13to

1.61)

t1/2

(h)7.74

(2.52to

33.5)

PK/PDtarget

attainmen

t(fo

urtim

esMIC

attainmen

tforPseudo

mon

asspp.)

Merop

enem

Day

<48

h(n

=7)

71%

Day

>48

h(n

=15)87%

Pipe

racilin-tazob

actam

Day

<48

h(n=12)66%

Day

>48

h(n

=9)

78%

Cefep

ime

Day

<48

h(n=7)

0%Day

>48

h(n

=4)

0%

Therecommen

deddo

sesforbroad-

spectrum

beta-lactam

sarege

nerally

insufficien

tto

maintaintherapeutic

serum

concen

trations

greaterthan

four

times

theMIC

ofP.aerugino

saApp

lyingresults

toothe

rMICs,the

observed

concen

trations

forall

antib

ioticswereadeq

uate

in90%

ofpatientson

lyforMICslower

than

the

clinicalbreakpoint

ofPseudo

mon

asspp.,w

hich

correspo

ndto

MICsof

sensitive

Enteroba

cteriaceae

Inthefirst48

hof

treatm

ent,29%,

34%,100%,and

62%

ofou

rpatients

treatedwith

merop

enem

,piperacillin-

tazoba

ctam

,cefepimeand

ceftazidim

e,respectiv

ely,

never

reachedthePK

target.A

fter4

8hof

treatm

ent,thedrug

concentrations

obtained

werehigh

er(significantly

different

onlyform

erop

enem

),bu

tthey

remainedinsufficientinmany

patients

Attheon

setof

sepsisin

patients

receivingCRR

T,similarbe

ta-lactam

dosesto

thoseused

intheabsence

ofrenalfailure

shou

ldbe

given

durin

gthefirst48

hof

therapy

Doseredu

ctionshou

ldbe

considered

thereafter

toavoiddrug

accumulation.

Con

side

ringthelarge

PKvariability,therapeutic

drug

mon

itorin

gof

beta-lactam

sshou

ldbe

perfo

rmed

toop

timizeantib

iotic

efficacy


Table

1PK/PDstud

iesof

beta-lactam

sin

patientsun

dergoing

CRRT(Con

tinued)

Stud

yEndp

oints

Antibiotic

Designandtype

ofCRR

TResults

Con

clusions

Ceftazidime

Day

<48

h(n=8)

38%

Day

>48

h(n=7)

71%

Robe

rts

etal.

[76]

Toevaluate

variabilityin

CLandVd

andto

assess

theeffect

ofCRR

Tprescriptio

non

extracorpo

realand

system

icantib

iotic

CLandVd

inpatientstreatedwith

CRR

Tof

different

intensities

Merop

enem

Pipe

racillin-tazobactam

Nestedcoho

rtprospe

ctive

multicen

terob

servationalP

Kstud

ywith

inarand

omized

controlledtrial

ofCRR

Tintensity

Patientswererand

omlyassign

edto

receivepo

st-dilutionalhem

odiafiltration

aseither

ahigh

er(40mL/kg

body

weigh

t/heffluentflowrate)o

rlow

er(25mL/kg

body

weigh

t/heffluent

flowrate)intensityrate

Samplingoccurred

each

day(1)

immed

iatelybe

fore

antib

iotic

dosing

,(2)aftercompletionof

their

intraven

ousinfusion

,and

(3)at

4h

aftercompletionof

infusion

Itoccurred

at65

timepo

intsfor

merop

enem

and29

timepo

intsfor

pipe

racillin-tazobactam

in24

patients

Meanhe

mod

iafiltrationclearanceof

merop

enem

,piperacillin,and

tazobactam

didno

tdiffersignificantly

betw

eenhigh

ervs

lower

CRRT

intensity:23(16–29)vs21

(15–28),

P=0.4802;22(21–31)vs24

(17–31),

P=0.9091;37(34–49)vs56

(41–66),

P=0.0642,respectively

System

icclearanceandVd

were

Merop

enem

38mL/min

(23–95)and

17.5L

Pipe

racillin59

mL/min

(37–115)

and

18.7L

Tazobactam

113mL/min

(45–248)

and49.3L

Theprescribed

intensity

ofCRR

Tdid

notadeq

uatelypredictextracorpo

real

clearanceor

Sd,CLs,Vd,or

half-life

System

icCLandelim

inationhalf-life

didno

tdifferaccordingto

CRR

Tdo

se,and

sotheCRR

Tprescriptio

nmay

notbe

useful

forgu

iding

antib

iotic

prescribing.

Inmanycases,

extracorpo

realCLaccoun

tedfor

morethan

30%

oftheob

served

system

icCLforthat

antib

iotic,w

hich

isasugg

estedthresholdfor

adjustmen

tof

thedo

sing

regimen

Drugmon

itorin

gmay

bethemost

practicalmetho

dforen

surin

gthat

antib

iotic

therapeutic

targetsare

achieved

incritically

illpatients

receivingCRR

T

Ohchi

etal.[77]

ToinvestigatePK

characteristicsof

dorip

enem

inpatientsreceiving

high

-flow

vsconven

tionalflow

intensity

CVV

HDF

Doripen

emProspe

ctive,ob

servationalstudy

Adu

ltICU

Twopatientswith

AKI

onhigh

-flow

CVV

HDF.Patientson

conven

tional

CVV

HDFwerede

scrib

edin

aprevious

stud

yDoripen

emadministrated

as250mg

sing

ledo

seinfusion

over

1h

Bloo

dsamples

werecollected

at1

(justpriorto

theen

dof

antib

iotic

infusion

),2,3,4,7,and12

hafter

initiatingtheinfusion

Highflow

CVV

HDFparameters:bloo

dflow

100mL/min;d

ialysate

flow

rate

1500

mL/h;

filtrationflow

rate

900mL/h

Con

ventionalC

VVHDF

AUC74.15±15.5mg.h/L

Cls58

±12.7mL/min

Cld

ialysis13.5±1.6mL/min

t1/2

7.9±3.7h

High-flow

CVV

HDF

AUC35.2mg.h/L

Cls118mL/min

Cld

ialysis41.9mL/min

t1/2

2.9h

Extracorpo

realclearanceincreasesin

prop

ortio

nwith

theintensity

dialysis

rate

Thedaily

dose

thus

mustbe

increased

to1.0–1.5g,thesamedo

sage

used

whencreatinineclearanceis>50

mL/

min

Arzuaga

etal.[78]

Tostud

ythePK

ofpipe

racillinand

tazobactam

durin

gCRR

Tin

ICU

patientswith

vario

usde

greesof

renalimpairm

ent.

Pipe

racilin-tazob

actam

Prospe

ctive,ob

servationalstudy

14adultICUpatientson

CVV

HDF,

grou

pedaccordingto

severity(CLC

R10

mL/min,10<CLC

R<50

mL/min,

andCLC

R>50

mL/min)

Pipe

racilin

4gandtazobactam

0.5g

wereadministrated

every6or

8h,

by20-m

inintraven

ousinfusion

Prefilter

bloo

dandultrafiltrate

samples

werecollected

at0,0.3,0.5,

0.75,1,3,6,and

8h(in

case

ofadministrationevery8h)

afterthe

CLC

R<10

mL/min

(n=4)

CLC

R:8.67

±2.31

mL/min

UFflow:27.1±7.8mL/min

Sc:PIP

0.42

±0.25;TZ0.76

±0.26

Cmax:PIP

365.6±232.3;TZ

38.4±

13.4mg/L

t1/2:PIP

7.8±4.2;TZ

7.9±3.0h

Cls:PIP

50.0±53.0;TZ50.4±

38.3mL/min

Hem

ofiltratio

nCl:PIP11.45±6.51;

TZ20.9±12.6mL/min

AUC:PIP

76143±49,748;TZ23218±

Thecontrib

utionof

thehemofiltratio

nclearanceto

thetotalclearance

increasedwith

thedegree

ofrenal

insufficiency.Correctdo

sesof

these

drug

sshou

ldtake

into

accoun

tthis

observationto

avoidclinicalfailures

dueto

unde

rdosing

Forb

othdrug

s,sig

nificantdifferences

weredo

cumentedinthemajority

ofthePK

parameterswhenpatientswith

CLCR

>50

mL/minwerecomparedto

patientswith

CLCR

≤10

mL/min


Table

1PK/PDstud

iesof

beta-lactam

sin

patientsun

dergoing

CRRT(Con

tinued)

Stud

yEndp

oints

Antibiotic

Designandtype

ofCRR

TResults

Con

clusions

administrationof

theantib

iotic.Tim

e0was

considered

justbe

fore

the

beginn

ingof

the20-min

infusion

27,943

mg.h/L

Vd:PIP

21.0±11.7;TZ18.9±7.1l

10<CLC

R>50

mL/min

(n=5)

CLC

R25.20±7.73

mL/min


Sc:PIP

0.38

±0.37;TZ0.73

±0.32

Cmax:PIP

244.5±122.1;TZ

31.5±

5.1mg/L

t1/2:PIP

4.2±2.3;TZ

4.1±0.9h

Cls:PIP

90.6±29.9;TZ68.2±

26.2mL/min

Hem

ofiltratio

nCl:PIP12.2±13.2;TZ

21.9±9.6mL/min

AUC:PIP

45445±25,525;TZ23218±

27,943

mg.h/L

Vd:PIP

26.8±19.8;TZ21.6±3.0l.

CLC

R>50

mL/min

(n=5)

CLC

R:82.40±20.03mL/min


Sc:PIP

0.23

±0.07;TZ0.86

±0.30

Cmax:PIP

160.6±93.2;TZ15.7±

6.6mg/L

t1/2:PIP

2.6±0.8

TZ5.0±3.9h

Cls:PIP

265.2±152.2;TZ

180.1±

73.9mL/min

Hem

ofiltratio

nCl:PIP4.8±3.3;TZ

19.6±15.3mL/min

AUC:PIP

17,328

±11,134;TZ2098

±1030

mg.h/L

Vd:PIP

44.9±20.4;TZ60.3±34.6l

t>MIC90

obtained

were100%

forall

thepathog

ensin

patientswith

creatin

ineclearance<10

mL/min.In

patientswith

acreatin

ineclearance

betw

een10

and50

mL/min,t>

MIC90

was

100%

forpathog

enswith

MIC90

≤32,b

uton

ly50%

for

microorganism

swith

anMIC90

of64.

How

ever,inpatientswith

creatin

ine

clearance>50

mL/min,aspiperacillin

elim

inationwas

faster,t>MIC90

was

only55.5%and16.6%forp

atho

gens

with

MIC90

values

of32

and

64,respectively

Theob

served

sievingcoefficient

ofpipe

racillinandtazobactam

plus

the

effluen

tam

ount

gave

arelevant

extracorpo

realclearanceon

lyin

the

severe

renalimpairm

entgrou

p,with

morethan

25%

oftotalclearance

for

both

drug

sTo

increase

thet>

MIC90

inde

x,pipe

racillin-tazobactam

combinatio

nevery4hcouldbe

abe

tter

dosage

regimen

inpatientspresen

tingCLC

R>50

mL/min

Islaet

al.[79]

Tode

scrib

ethePK

ofmerop

enem

incritically

illpatientswith

different

degreesof

renalimpairm

ent

unde

rgoing

CVV

HFor

CVV

HD

Merop

enem

Prospe

ctive,ob

servationalstudy

20adultICUpatientson

CVV

HFor

CVV

HDF

Group

edinto

3catego

riesaccording

totherenalfun

ction:

7with

severe

failure,C

lCrless

than

10mL/min

Nosign

ificant

differences

depe

nding

onrenalimpairm

entwerefoun

din

theSc.N

odifferences

werefoun

din

theSc

obtained

byCVV

HFandthe

Saob

tained

byCVV

HD;b

oth

mem

branes

show

edasimilar

Differen

cesin

merop

enem

PKin

critically

illpatientsun

dergoing

CRR

Twith

different

degreesof

renal

impairm

enthave

been

observed

,andthey

shou

ldbe

takeninto

accoun

twhe

ndo

sing

critically

ill


Table

1PK/PDstud

iesof

beta-lactam

sin

patientsun

dergoing

CRRT(Con

tinued)

Stud

yEndp

oints

Antibiotic

Designandtype

ofCRR

TResults

Con

clusions

(group

I);7with

mod

eratefailure,

ClCr10

to50

mL/min

(group

II);and

6with

ClCrgreaterthan

50mL/min

(group

III)

Bloo

dflow

rate

110–220mL/min;

dialysateflow

rate

500or

1000

mL/

min;ultrafiltrate

800–2500

mL/h

Patientsreceived

500,1000,or

2000

mgof

merop

enem

intraven

ouslyevery6or

8hand

infusedover

20min

Bloo

dwas

obtained

from

aprefilter

device

immed

iatelybe

fore

dosing

,at

theen

dof

theinfusion

,and

at20,

30,and

45min

and1,3,and6h

afterthebe

ginn

ingof

theinfusion

.Ano

ther

samplewas

collected

8h

afterthebe

ginn

ingof

theinfusion

inpatientsto

who

mmerop

enem

was

administeredevery8h

Simultane

ously,dialysate-ultrafiltrate

samples

weretakendirectlyfro

mthe

dialysate-ultrafiltrate

device

perm

eabilityto

merop

enem

Totalclearance

was

sign

ificantly

high

erin

grou

pIIIthan

intheothe

rtw

ogrou

ps.Thisfinding

couldbe

attributableto

thelower

t1/2

(1.51±0.52

hin

grou

pIIIversus

2.73

±0.68

hand3.72

±0.82

hin

grou

psIIandI,respectively)

andto

thehigh

Vdob

served

inthose

patients(1.31±0.90

L/kg

ingrou

pIII,

0.37

±0.10

L/kg

ingrou

pII,and

0.57

±0.29

L/kg

ingrou

pI)

Thecontrib

utionof

CRR

Tto

total

clearancediminishe

din

theextent

that

CLC

Rincreased.

Alth

ough

there

wereno

statisticallysign

ificant

differences

betw

eengrou

psIand

II,Cl CRRTwas

sign

ificantlylower

ingrou

pIII

Ingrou

pIp

atients,trou

ghplasma

concen

trations

wereabove4μg

/mL,

with

theexceptionof

theon

lypatient

who

received

500mg/8h.

Ingrou

pII,plasmaconcen

trations

were

above2μg

/mLdu

ringtheen

tire

dose

interval,excep

tin

thepatient

towho

m1000

mg/8hwas

administered

Inspite

ofthehigh

erdo

sesthe

patientsof

grou

pIIIreceived

,4of

6patientsshow

edconcen

trations

below

0.5μg

/mL

patients

Inthosepatientswith

norenal

impairm

enttheriskof

unde

rdosing

andclinicalfailure

isim

portant,and

theadministrationof

merop

enem

2000

mgevery8hdidno

treach

plasmalevelsto

ensure

adeq

uate

T>MIC

values

againstmanybacteria

Ulldem

olins

etal.[80]

Tode

scrib

ethePKsof

merop

enem

incritically

illpatientswith

septic

shockandCRR

T,to

iden

tifythe

sourcesof

PKvariabilityin

these

patients,andto

perfo

rmdifferent

dosing

simulations

toassess

their

prob

ability

oftarget

attainmen

tby

MIC,inorde

rto

provideem

pirical

dosing

recommen

datio

nsbasedon

clinicalcharacteristics

Merop

enem

Prospe

ctive,ob

servational,

multicen

trestud

y30

adultICUpatientswith

septic

shockandCRR

T,either

CVV

HF(n

=4)

orCVV

HDF(n

=26)

Patientswereprescribed

merop

enem

at500mgq1

2hover

30min

(n=1);500

mgq8

hover

30min

(n=2)

oras

a3-hinfusion

(n=3);500

mgq6

has

a3-hinfusion

(n=1);1000mg

q12h

over

30min

(n=6)

asa3-h

infusion

(n=1)

oras

a4-hinfusion

(n=1);1000mgq8

hover

30min

(n=8)

asa3-hinfusion

(n=5)

oras

a4h-infusion

(n=1);or2000

mg

q8hover

30min

(n=1)

Bloo

dsamples

werecollected

at24

hof

CRR

Tandmerop

enem

Thestud

ymod

elfailedto

iden

tify

CRR

Tintensity

tobe

asign

ificant

mod

ifier

ofmerop

enem

CL,which

may

lead

tothehypo

thesisthat

even

thelowestCRR

Tintensities

stud

iedmay

been

ough

tomaxim

ize

merop

enem

clearanceandthat

high

erintensities

may

addlittle

tototalm

erop

enem

CL

Therewereno

differences

betw

een

CRR

Ttechniqu

es,likelybe

causeof

theun

derrep

resentationof

CVV

HF

(4ou

tof

30patients)in

thestud

ypo

pulatio

nFortheattainmen

tof

aPD

target

of100%

oftheT>MIC,fixed

doses

wou

ldbe

requ

ired,

depe

ndingon

theMIC

ofthebacteria,b

utthe

infusion

timewou

ldde

pend

on

Popu

latio

nPK

mod

elsuccessfully

iden

tifiedresidu

aldiuresisto

bea

mod

ifier

oftotalm

erop

enem

CL

CRR

Tintensity

didno

tsign

ificantly

mod

ifymerop

enem

CL,forwhich

dose

adjustmen

tsbasedon

intensity

seem

tobe

unne

cessary

Given

acertainMIC,sim

ulations

show

edthat

merop

enem

dose

titratio

nconsideringresidu

aldiuresis

was

advantageous

forthe

attainment

of100%

oftheT>MIC

asaPD

target.

Ifclassic

PDtargets(40%

oftheT>

MIC)w

eretargeted,a

standard

dose

of500mgq8has

a30-m

inbo

lus

wou

ldbe

sufficient,regardlessof

urineou

tput


Table

1PK/PDstud

iesof

beta-lactam

sin

patientsun

dergoing

CRRT(Con

tinued)

Stud

yEndp

oints

Antibiotic

Designandtype

ofCRR

TResults

Con

clusions

therapy.Forbo

lussampling,

6samples

werecollected

at10

min

pre-do

se;at0,15,and

60min

and

betw

een3and6haftertheen

dof

theinfusion

;and

justbe

fore

thene

xtdo

se.For

extend

edinfusio

nsampling,

samples

werecollected

at10

min

pre-do

se;0,60,and120minafterthe

endof

theinfusio

n;andjustbefore

thenextdo

seCRR

Tsettings:the

med

ianintensity

onthedayof

thestud

ywas

34.7mL/kg/h

(rang

e,18.7to

60.1mL/kg/h),andthemed

ian

bloo

dflow

was

200mL/min

(rang

e,130to

250mL/min)

residu

aldiuresis:o

ligo-anuricpatients

wou

ldbe

nefit

from

a30-m

inbo

lus,

whilea3-hextend

edinfusion

wou

ldbe

moreapprop

riate

forthose

patientswith

preserveddiuresis

Fortheattainmen

tof

theclassicPD

target

forcarbapen

ems(40%

ofthe

T>MIC),astandard

dose

of500mg

q8has

abo

lusover

30min

wou

ldbe

sufficien

tforallcases

Fortheattainmen

tof

amore

aggressive

target,suchas

aCmin/

MIC

ratio

of5,do

sesof

1000

mg

q8has

a3-hinfusion

orhigh

erwou

ldbe

requ

ired

Boum

anet

al.

[81]

Tocompare

theob

served

Cl CVVHF

(calculatedfro

mmeasureddata)and

thepred

ictedCl CVVHF(calculated

from

theF U

P)

Tode

term

inewhe

ther

dose

adjustmen

taccordingto

the

pred

ictedCVV

Hremovalprovides

anestim

ateas

reliableas

that

according

totheob

served

CVV

Hremoval

Amoxicillin

Ceftazidime

Flucloxacillin

Prospe

ctive,ob

servationalstudy

45adultICUoligoanu

ricpatientson

CVV

HF

Duringthesamplingpe

riodasing

leantim

icrobialdrug

was

administered

to31

patients,tw

odrug

sto

9patients,andacombinatio

nof

3to

5Dosages

were:am

oxicilin1000

mg

q6h;

ceftazidim

e1000

mgq6

-12h;

flucloxacillin

2000

mgq4

-6h

Bloo

dflow

rate

was

150mL/min

and

warmed

substitutionfluidswere

administeredin

pred

ilutio

nat

aflow

rate

of2000

mL/h.

Ifane

gativefluid

balancewas

requ

ired,theultrafiltration

flow

was

increasedan

dthe

substitutionflo

wwas

constant

Bloo

dsamples

werecollected

from

theafferent

(pre-hem

ofilter)and

efferent

(post-he

mofilter)lineof

the

extracorpo

realcircuitandfro

mthe

ultrafiltrate

line.Samples

were

collected

at2,4,and6hforagen

tsgivenevery6h;at

2,4,and8hfor

agen

tsgivenevery8h;andat

2,6,

and10

hforagen

tsgivenevery12

or24

h

Allthestud

iedagen

tswereeasily

filtered(SC>0.7)

with

theexception

offlucloxacillin

Therewas

ahigh

interin

dividu

alvariabilityin

theSC

values

ofthe

stud

ieddrug

s,in

particular

for

ceftazidim

eandto

alesser

degree

foram

oxycillin

andflucloxacillin

Thecorrelationbe

tweenob

served

andpred

ictedclearancewas

sign

ificant

(P=0.003)

onlywhe

nall

drug

swerecombine

d,no

tforthe

individu

alantim

icrobialdrug

s.Despite

theno

nsignificant

correlation,

thedifferencebe

tween

pred

ictedandob

served

clearance

foralld

rugs

was

small,with

the

exceptionof

ceftazidim

e

Therewas

nosign

ificant

correlation

betw

eenpred

ictedandob

served

CVV

Hdrug

removal.H

owever,for

clinicalpractice,do

seadjustmen

taccordingto

thepred

ictedCVV

Hremovalprovides

amorereliable

estim

atethan

that

accordingto

the

observed

CVV

Hremoval

Alth

ough

thereisinterpatient

variabilitybe

tweentheob

served

and

pred

ictedCl CVVHFvalues

forsome

antib

iotics,its

effect

ondo

sing

strategies

isno

tne

cessarily

clinically

relevant:flucloxacillin

hasan

impo

rtantno

n-renalelim

ination

route,andthereforetheFrCVVHF

valuewas

extrem

elylow

andno

taffected

bythewideinterin

dividu

alvariatio

nin

observed

Cl CVVHF.Also,

widetherapeutic

rang

e,such

aswith

ceftazidim

e,makes

itsafe

tousethe

pred

ictedClCVVHFford

oseadjustment

AKI

acutekidn

eyinjury,A

UCarea

unde

rthecurve,

ClCr

creatin

ineclearance,

CLssystem

icclearance,

Cldialysisextracorpo

real

clearance,

Cmax

maxim

alconcen

tration,

Cmin

minim

alconcen

tration,

CRRT

continuo

usrena

lrep

lacemen

ttherap

y,CV

VHFcontinuo

usveno

us-ven

oushe

mofiltratio

n,CV

VHDcontinuo

usveno

us-ven

ousha

emod

ialysis,CV

VHDFcontinuo

usveno

-ven

ous

hemod

iafiltration,

Fupun

boun

dfractio

nof

adrug

,MIC

minim

alinhibitory

concen

tration,

PTAprob

ability

oftarget

attainmen

t,Ssaturatio

ncoefficient,Scsievingcoefficient,t1/2ha

lf-life,

T>MIC

timeab

oveMIC,U

FRultrafiltratio

nrate,V

dvo

lume

ofdistrib

ution


Table

2PK/PDstud

iesof

beta-lactam

sin

patientswith

sustaine

dlow-efficien

cydialysisor

extend

eddaily

dialysis

Stud

yEndp

oints

Antibiotic

Design

Results

Con

clusions

Kielstein

etal.[82]

Toevaluate

PKof

merop

enem

incritically

illpatientswith

renal

failure

unde

rgoing

EDD

Merop

enem

Prospe

ctiveclinicalstud

yAdu

ltICUpatientswith

anuricacute

renalfailure

beingtreatedwith

EDD

andreceivingmerop

enem

(n=10)

Merop

enem

administeredas

1gdo

se,

asan

intraven

ousinfusion

over

ape

riodof

30mins,6hbe

fore

EDD

was

started

Bloo

dsamples

weredraw

nbe

fore

administrationof

thedrug

;at0.5,

1,2,4,and6hafterits

administration;

before

EDD;d

uringED

D,attim

epo

ints2,4,and6h;at

theen

dof

EDD;and

at0.5,1,3,and8hafter

EDD.A

ddition

albloo

dsamples

were

draw

npre-

andpo

st-dialyzerin

orde

rto

calculatethedialyzer

clearance

Theaverage(m

ean±SD

)dialysistim

edu

ringthestud

ywas

480±6min,

andmeanbloo

dandcoun

tercurrent

dialysateflow

was

160±3mL/min

T1/2offwas

8.7h[4.7–30]

T1/2on

was

3.7h[2.1–4.7]

Vdwas

0.72

L/kg

[0.35–2.78]

CLoff5.01

L/h[2.44–11.15]

CLdialw

as2.3L/h[0.7–3.7]

(estim

ated

from

thedrug

amou

ntrecoveredin

thedialysate)

and5.1L/h[4.3–5.7](estim

ated

from

drug

concen

trations

before

andafter

applicationof

thedialysismem

brane)

Merop

enem

issign

ificantlyelim

inated

byED

D.C

omparedwith

PKresults

intheliteratureforinterm

itten

tdialysis

andCRRT,do

sing

regimen

scann

otbe

used

forcritically

illsepticpatients

with

renalfailure

beingtreated

with

EDD

EDDelim

inates

merop

enem

atleast

toan

extent

similarto

CVVH.Thu

s,ph

ysicians

runtheriskof

unde

rdosing.

Ado

seof

0.5to

1.0gmerop

enem

every8hisrecommen

ded.

Theexact

dose

shou

ldbe

tailoredaccordingto

weigh

tandseverityof

illne

ssas

well

asto

thecurren

tMIC

againstthe

incrim

inated

bacteria.W

hene

ver

possible,the

rape

uticdrug

mon

itorin

gshou

ldbe

perfo

rmed

Lorenzen

etal.[83]

Theaimsof

thisstud

ywereto

evaluate

thePK

ofam

picillin/sulbactam

incritically

illpatientswith

AKI

unde

rgoing

extend

eddialysisandto

establishado

sing

recommen

datio

nfor

thistreatm

entmetho

d

Ampicilin-sulbactam

Prospe

ctive,op

en-labe

l,ob

servationalstudy


anuricAKI

PKafterasing

ledo

seof

ampicillin/

sulbactam

(2g/1g)

over

ape

riodof

30min

was

obtained

in12

patients.

Multip

le-dosePK

after4days

oftw

ice-

daily

ampicillin/sulbactam

(2g/1g)

was

obtained

inthreepatients.The

averagedialysistim

ewas

442±77

min

andmeanbloo

dandcoun

ter

curren

tdialysateflow

was

162±6

mL/min,resultin

gin

ameanurea

redu

ctionratio

of50.1%

±2.7%

.ED

was

started3haftertheen

dof

the

ampicillin/sulbactam

infusion

Cmax

280.9±174.9mg/L

Tmax

0.5h

AUClast847.5±499.5mg.h/L

t1/2

2.8±0.8

Vd(L)13.1±11.1

CLtot

61.1±55.2mL/min

CLdial80.1±7.7mL/min

Ampicillin/sulbactam

iselim

inated

byED

Current

dosing

recommen

datio

nsfro

mpatientsun

dergoing

IHD(3

gevery24

h)wou

ldcauseasign

ificant

unde

rdosingof

thedrug

inpatients

treatedwith

EDAmpicillin/sulbactam

concen

trations

exceed

edMIC90

values

ofEnterobacteriaceae,suchas

Escherichia

colior

Klebsiella

pneumon

iae(M

IC90

<2.0mg/L)

orEnterococcus

faecalis

(MIC90

=2.0mg/L),o

nlyfor8h

(app

roximately30%

ofthedo

sing

intervalforpatientson

interm

itten

the

mod

ialysis)afterstartof

infusion

.Ado

sage

of3gevery12

hin

patients

unde

rgoing

EDdo

esno

tlead

toa

sign

ificant

accumulationof

thedrug

Burkhardt

etal.[84]

Toevaluate

PKof

ertape

nem,w

ithon

ce-dailydo

sing

,incritically

illpatients

with

anuricacuterenalfailure

unde

rgo-

ingED

D

Ertape

nem

Prospe

ctive,op

en-labe

lstudy

6adultICUpatientsun

dergoing

EDD

treatedwith

1gertape

nem

asa

sing

leintraven

ousdo

seBloo

dsamples

werecollected

before

ertape

nem

infusion

and0.5,1,2,4,6,

8haftertheen

dof

theinfusion

and

also

2,4,6,and8hafterthestartof

EDD.A

ddition

albloo

dsamples

were

draw

npre-

andpo

st-dialysisin

orde

rto

calculatethedialyzer

clearance.

Tostud

ypo

st-EDDPK,sam

ples

were

draw

n0.5,1,3,and8hafterthe

endof

EDD

Cmax

81.3±12.1mg/L

AUC0-inf687.4±212.0mg.h/L

T1/2off18.9±5.4h

T1/2on

6.7±0.4h

Vd(L)15.9±3.2

CLoff19.3±11.4mL/min

CLdial49.5±10.9mL/min

T>MIC

was

100%

(MIC90

≤1mg/L)

and85%

(MIC90

≤2mg/L)

1gertape

nem

perdayto

critically

illpatientswith

ARF

intheICUthat

unde

rgoED

Disne

cessaryto

ensure

optim

alfre

econcen

trations

ofertape

nem.A

redu

ctionof

thedo

seisno

tsupp

ortedby

ourdata.Further

dosing

recommen

datio

nsforpatients

with

renalfailure

intheICUtreated

with

such

effectivemod

esof

renal

replacem

enttherapyshou

ldbe

develope

dto

avoidexcess

mortality

dueto

unde

r-do

sing

oflife-saving

med

ication


Table

2PK/PDstud

iesof

beta-lactam

sin

patientswith

sustaine

dlow-efficien

cydialysisor

extend

eddaily

dialysis(Con

tinued)

Stud

yEndp

oints

Antibiotic

Design

Results

Con

clusions

Tamme

etal.[85]

Tode

scrib

ethePK

ofpipe

racillinand

tazobactam

durin

gextend

edhigh

volumehe

mod

iafiltrationto

define

optim

aldo

sing

Pipe

racilin-

tazobactam

Prospe

ctive,ob

servationalstudy


sepsis

andAKIrequ

iring

CRR

TAsing

ledo

seof

4000

mgof

pipe

racillinand500mgtazobactam

was

administeredas

a30-m

inintraven

ousinfusion

1hafterthe

startof

HVH

DF

Bloo

dsamples

of4mLwerecollected

before

andim

med

iatelyaftertheen

dof

pipe

racillin/tazobactam

infusion

and60,90,120,150,180,

240,300,360,420,and480min

afterthestartof

drug

administration

Theplasmaconcen

tration–

time

profilesof

pipe

racillinandespe

cially

tazobactam

demon

stratedhigh

interin

dividu

alvariability

Forpipe

racilin

CL(rang

e)6.9L/h(6.1–7.9)

Vdcentralcom

partmen

t(rang

e)9.0L(7.4–11.0)

Vdpe

riphe

ralcom

partmen

t(rang

e)11.2L(8.9–14.2)

Fortazobactam

CL(rang

e)5.1L/h(4.1–6.3)

Vdcentralcom

partmen

t(rang

e)8.6L(6.9–10.7)

Vdpe

riphe

ralcom

partmen

t(rang

e)8.9L(6.6–12.0)

Using

Mon

teCarlo

simulation,

the

prob

ability

of100%

fT>MIC

target

attainmen

tforpipe

racillin/tazobactam

4.5gdo

sedevery6and8has

4-h

infusion

were88.6%

and61.0%,

respectively,forMIC

16mg/l

App

licationof

extend

edHVH

DFforthe

treatm

entof

AKI

insepticshock

patientsresults

inconsiderable

clearanceof

pipe

racillinand

tazobactam

Pipe

racillin/tazobactam

dosesof

4.5g,

administeredevery8has

0.5-hinfusion

durin

gHVH

DF,en

suredmorethan

80%

prob

ability

ofattainingthe50%

fT>MIC

target

for

interm

ediatelysuscep

tiblebacteria(M

IC16

mg/l)

Whileaimingfor100%

fT>MIC

of16

mg/l,increasing

dosesto

4.5gevery6handprolon

ging

the

infusion

timeto

4hwou

ldbe

necessary

AKI

acutekidn

eyinjury,A

RFacuterena

lfailure,C

Ldiald

ialysisclearance,CLoffdrug

clearancewith

outdialysis,EDDextend

edda

ilydialysis,ICU

intensivecare

unit,

SDstan

dard

deviation,

SLED

sustaine

dlow-efficiencydialysis,T1/2o

ffha

lf-lifebe

fore/after

EDD,T1/2o

nha

lf-lifedu

ringED

D,V

dvo

lumeof

distrib

ution


Table

3PK/PDstud

iesof

beta-lactam

sin

patientswith

extracorpo

realmem

braneoxygen

ation

Stud

yEndp

oints

Antibiotic

Design

Results

Con

clusions

Don

adello

etal.[100]

Toinvestigatewhe

ther

ECMOcouldalterthe

pharmacokineticsof

merop

enem

andpipe

racillin/

tazobactam

inICUpatients

Merop

enem

Pipe

racilin/

tazobactam

Retrospe

ctive,case-con

trol

stud

yin

67ICUpatients

Antibioticsdaily

dosing

was

done

accordingto

renald

osing

Beta-lactam

plasmaconcen

trations

weremeasuredT2

andjustbe

fore

administrationof

thesubseq

uent

dose

T0TD

Mresults

inEC

MOpatients

(VVor

VA)werematched

(1:1)to

TDM

results

ofno

n-EC

MOpatients

(total41

TDM

matches)accordingto

thefollowingcriteria:d

rugregimen

;renalfun

ction(sam

eClCror,ifon

CRR

T,sameCRR

Tintensity

with

anacceptable

differenceof

10%);totalb

odyweigh

t;SO

FAscoreat

thetim

eof

treatm

ent

initiation;

age

Forbo

thantib

iotics,therewerenu

merical

differences

butwith

nostatisticalsign

ificance

inV d,t1/2andCLbe

tweenEC

MOpatients

andcontrols

Theprop

ortio

nsof

insufficien

t(13/41

vs12/41),

adeq

uate

(15/41

vs19/41),and

excessive

(13/41

vs10/41)

drug

concen

trations

were

similarin

ECMOandcontrolp

atients

PKparametersandTD

Mresults

were

notsign

ificantlyalteredin

ECMOpatients

comparedwith

controlICUpatients

Alm

ost30%

oftheoverallTDM

results

were

associated

with

insufficien

tantib

iotic

concen

trations

toop

timallytreatP.aerugino

sa

Shekar

etal.[101]

Tode

scrib

esing

le-dosemerop

ene

mPK

durin

gEC

MOusing

critically

illpatientswith

sepsis

andno

treceivingEC

MO

ascontrols

Merop

enem

Ope

n-labe

l,de

scrip

tive,

matched

-coh

ortPK

stud

yAdu

ltICUpatientson

ECMO(noRR

Tn=6;on

RRTn=5)

andcontrols

(norenald

ysfunctio

nn=5;on

RRTn=5)

Merop

enem

dosesin

ECMO:

1g8/8h(n

=8);1.5g8/8h(n

=2)

and2gbo

lus;and1g8/8h(n

=1)

Con

trols:1.5gbo

lusand1g8/8h

(norenald

ysfunctio

n);1

g8/8h

Con

trolsvs

ECMO

Cmax:65.4(58.7–74.4)vs

55.3(37.8–60.4)mg/L

Cmin:4.2(0.0–5.7)vs

7.2(4.0–17.2)

mg/L

Vd:0.45±0.17

vs0.41

±0.13

L/kg,P

=0.21

Clearance:7.9±5.9vs

11.7±6.5L/h,P=0.18

ECMOpatients,trou

ghconcen

trations

>2mg/L

wereachieved

inallp

atients.Throug

hconcen

trations

>8mg/L(targe

tingless

suscep

tiblemicroorganism

s)wereachieved

inon

ly8ou

tof

11patients,5of

them

being

onRR

T

Standard

merop

enem

dosing

(1gIV

8-ho

urly)as

aninterm

itten

tbo

lusinfusion

inEC

MOpatients

islikelyto

resultin

drug

concen

trations

sufficien

tto

treathigh

lysuscep

tibleGram-neg

ative

pathog

ens

How

ever,w

hentreatin

gless

suscep

tibleP.

aerugino

sa(M

IC90

8mg/L)

andAcinetobacter

species(M

IC90

16mg/L)

high

ermerop

enem

dosesmay

have

tobe

considered

Welsch

etal.[102]

Torepo

rtthecasesof

two

patientson

VVEC

MOfor

refractoryARD

Sfollowinglung

transplantationandtreated

empiricallywith

imipen

em

Imipen

emCaserepo

rtIm

ipen

em1gevery6h

Serum

andmini-BALsamples

(native

andtransplant

lung

)collected

atsteady

stateafter2days

oftherapyim

med

i-atelybe

fore

thefifth

drug

dose

Enteroba

ctercloa

caewas

isolated

from

therespiratory

sampleof

patient

1and

Klebsiella

pneumon

iaewas

isolated

from

therespiratory

sampleof

patient

2MIC

ofthetw

oisolated

strainswere

0.125and0.25

mg/L,respectively

BALconcen

trations

were

unde

tectable(<

0.5mg/L)

Serum

T>MIC

ofbo

thmicroorganism

swas

100%

Con

side

ringmoreresistantmicroorganism

s,such

asP.aerugino

sawith

MIC

>2mg/L,theprob

ability

ofachievingafractionaltim

eaboveMIC

>50%

or100%

was

also

high

Therewas

greatvariabilityin

theresidu

alserum

concen

trationof

imipen

embe

tweenthetw

opatients

Anelevated

dosing

regimen

(4g/24

h)ismore

likelyto

optim

izedrug

expo

sure,and

therapeutic

drug

mon

itorin

gisrecommen

ded

ARD

Sacuterespira

tory

distress

synd

rome,

BALbron

chial-a

lveo

larlavage

,CLclearance,ClCr

creatin

ineclearance,

CRRT

continuo

usrena

lrep

lacemen

ttherap

y,EC

MOextracorpo

real

mem

bran

eoxyg

enation,

ICUintensivecare

unit,

MIC

minim

alinhibitory

concen

tration,

RRTrena

lrep

lacemen

ttherap

y,SO

FAsequ

entia

lorgan

failure

assessmen

t,T>MIC

percen

tage

oftim

eab

oveminim

alinhibitory

concen

tration,

T00hafterthestartof

infusion

,T22hafterthestartof

infusion

,TDM

therap

eutic

drug

mon

itorin

g,V d

volumeof

distrib

ution,

veno

us-arterial,VV

veno

us-ven

ous


However results are conflicting concerning decreasedmortality and bacteriological and clinical cure rates [144].A sub-analysis from the DALI study compared intermit-tent bolus vs prolonged infusions of beta-lactams in pa-tients with respiratory infection and concluded thatpatients receiving beta-lactams via prolonged infusiondemonstrated significantly better 30-day survival [145].Falagas et al. [114] conducted a meta-analysis of 14

studies comparing continuous and short-term infusionof carbapenems and piperacilin-tazobactam, involving1229 patients. Mortality was lower among patients re-ceiving extended or continuous infusion of carbapenemsor piperacillin/tazobactam compared to those receivingshort-term infusion (risk ratio (RR) 0.59, 95% confidenceinterval (CI) 0.41–0.83). Patients with pneumonia whoreceived extended or continuous infusion had lowermortality than those receiving short-term infusion (RR0.50, 95% CI 0.26–0.96) [114].An interesting retrospective study by Huang et al. [120]

reviewed 68 neurosurgical patients with post-operativeintracranial infections treated with 4 g/day cefepime over24 h as a continuous infusion (CI; n = 34) or 2 g every 12 has intermittent infusion (II; n = 34). CI controlled the intra-cranial infection more rapidly and effectively than II (6.6 ±1.9 days vs 7.8 ± 2.6 days; P = 0.036). PD targets were moreachievable with CI: for plasma cefepime concentrations,the percentage fT >MIC in the CI group was higher thanin the II group (for MICs of 8 μg/mL, 100% vs 75%, re-spectively). For cerebral spinal fluid (CSF) cefepime con-centrations, the percentage fT >MIC in the CI group washigher than in the II group (for MICs of 4 μg/mL and8 μg/mL, 83.3% and 75% vs 25% and 0%, respectively)[120].De Waele et al. [27] reviewed 343 patients from 68 ICUs

across ten countries and concluded that use of intermit-tent infusion was the most significant factor associatedwith target non-attainment, for both 50% and 100% fT >MIC. Other risk factors for target non-attainment wereClCr, recent surgery, and timing from initial antibiotictherapy and sampling. However, the type of infusion wassuch a significant covariate in the model that it eliminatedthe effects of other variables [27].

Site of infectionUsually drug concentrations in blood are used to deter-mine PD parameters, such as percentage of time druglevels exceed the MIC and peak drug AUC/MIC level,due to the relative accessibility of this body fluid. Be-cause infection usually occurs at extravascular sites, theuse of drug concentrations in blood is only satisfactory ifblood levels are an adequate surrogate for levels at thesite of infection [13]. In septic shock, blood misdistribu-tion in the microcirculation might decrease antibioticconcentration at the infection site [1].

Boyadjiev et al. [146] studied ertapenem penetrationinto muscle in mechanically ventilated patients and con-cluded that average muscle free-ertapenem concentra-tions were above the MIC values of targeted pathogensexcept in a few patients. Karjagin et al. [147] evaluatedthe PK/PD relations of meropenem in plasma and peri-toneal fluid by microdialysis and showed that area underthe concentration–time curve was lower in peritonealfluid than in plasma, concluding that in patients with se-vere peritonitis associated with septic shock, a dosingregimen of 1 g infused over 20 min every 8 h is sufficientagainst susceptible bacteria, but not always against inter-mediately susceptible bacteria. Also, beta-lactam PK isvariable between plasma and subcutaneous interstitialfluid in septic patients [148]. Thus, prediction of micro-biological outcome based on concentrations in plasmaresults in overestimation of antimicrobial activity at thesite of infection.Special anatomic barriers (e.g., brain, eye, and pros-

tate) can result in drug levels being much lower thanfree drug levels in plasma [13]. The combination of tightjunctions and active transport systems that form theblood–brain barrier creates a substantial impediment tothe penetration of most antibiotics into the CSF. How-ever, the presence of inflammation within the meningessignificantly alters the permeability of the blood–brainbarrier, increasing CSF exposure for the majority of anti-biotics [20]. For meningitis, CSF levels are appropriatefor determination of PD parameters.Very few studies have investigated PK/PD issues in the

CSF (Table 4). Five case reports, one randomized clinicaltrial in a paediatric population, and three prospectiveobservational studies found good probability of target at-tainment for susceptible strains but standard dosing maynot be optimal for less susceptible strains. Prolongedand/or continuous infusion is of benefit in the attemptto achieve PD targets. No data regarding intermittentversus continuous CSF ventricular drainage were foundand conceptually these two types of drainage may alterthe beta-lactam PK profile.There is very sparse data on possible surrogate central

nervous system penetration factors for beta-lactams, sono conclusions can be made. We recommend to usehigher than standard dosing, preferably with continuousor prolonged infusions, especially when treating less sus-ceptible bacterial strains. Toxicity did not increase at in-creased doses. Finally, none of these studies addressedclinical outcome.Though there are PK models of plasma concentrations

of beta-lactams specifically for the critically ill popula-tion with pneumonia, it is suggested that epithelial liningfluid (ELF) concentrations are important determinantsof efficacy of treatment of bacterial pneumonia.ELF-to-serum penetration ratios may vary widely among


Table

4PK/PDstud

iesof

beta-lactam

sin

cerebralspinalfluid

Stud

yEndp

oints

Antibiotic

Design

Results

Con

clusions

Goldw

ater

etal.[149]

Toevaluate

antib

iotic

CSF

pene

trationand

antim

icrobialefficacy

Ceftriaxone

Cefotaxim

e

Rand

omised

,ope

n,comparativetrial

120paed

iatricpatientswith

men

ingitis,33with

repe

ated

lumbarpu

ncture

atdifferent

times

CRO

100mg/kg

once

daily;

CTX

50mg/kg

every6h

All33

repe

ated

lumbarpu

nctures

weresterile

ThelowestCSF

levelrecorde

d(0.45μg

/mLforCTX)was

45tim

estheMIC

(0.01μg

/mL).The

high

est

levels(24–35

μg/m

LforCRO

)were

upto

8750

times

theMIC

ofthe

patient’scausativeorganism

Antibiotic

levelsachieved

inCSF

weretherapeutic,b

eing

wellabo

vetheMIC

forallo

rganisms

encoun

tered

CSF

cellcoun

thadno

apparent

influen

ceon

antib

iotic

levels

Lonsdale

etal.[150]

Toillustrateissues

inthe

managem

entof

CSF

antib

iotic

concen

trations

Merop

enem

Caserepo

rtNeurosurgicalpatient

with

externalventricular

drain-relatedventriculitis

Ade

quateplasmathroug

hconcen

trations

achievableafterincreasing

dosing

to2g,

four

times

daily

CSF

concen

trations

ofmerop

enem

weresimilarto

thoseseen

inplasma

Therewerevariatio

nsin

CSF

drug

pene

tration

Achieving

CSF

therapeutic

antib

acterialcon

centratio

nsin

neurosurgicalcriticallyillpatientsis

difficult

Standard

antib

acterialp

rescrip

tion

ispo

tentially

flawed

inthissetting,

sugg

estin

gthene

edfortherapeutic

drug

mon

itorin

g

Abd

ul-Aziz

etal.[151]

Torepo

rtthedifficulty

inachieving

andmaintaining

target

antib

iotic

expo

sure

incritically

illpatients

with

deep

-seede

dinfections

Flucloxacillin

Caserepo

rtCriticalcare

patient

with

CNSinfection

Trou

ghplasmaconcen

trations

were

below

theMIC;C

SFconcen

trations

wereun

detectable(interm

itten

tdo

ses2g6/6h)

With

continuo

usinfusion

and

increasing

thedo

seto

20gdaily,

theplasmaandCSF

levelsbe

camede

tectable,albeit

lower

than

thepred

efined

targets

Antibiotic

pharmacokineticsmay

besign

ificantlyalteredin

critically

illpatients

App

lyingcontinuo

usinfusion

and

mon

itorin

gplasmaandCSF

levels

isof

sign

ificanceto

optim

ize

antib

iotic

delivery

Cieset

al.

[152]

Tode

scrib

etheph

armacokinetics

ofcontinuo

us-in

fusion

ofmerop

enem

Merop

enem

Caserepo

rt.

Paed

iatricpatient

with

ventriculitis

Serum

levelswere12

μg/m

Lat

2hand“und

etectable”

at4h,

with

CSF

levelsof

1and0.5μg

/mLat

2and4h,

respectively(M

IC<0.25)

Oncontinuo

usinfusion

,serum

,andCSF

levelswereno

tedto

be13

and0.5μg

/mL,respectively

Thecontinuo

us-in

fusion

dosing

regimen

allowed

for100%

prob

ability

oftarget

attainmen

tin

theserum

andCSF

andasuccessful

clinicalou

tcom

e

Dahyot-

Fizelier

etal.[153]

Tode

scrib

ebraindistrib

ution

ofcefotaximeby

microdialysis

inpatientswith

acutebraininjury

Cefotaxim

eObservatio

nal,

prospe

ctivestud

y5ICUpatientswith

acutebraininjury,treated

forlung

infection

Cefotaxim

e2g8/8h

MeanAUC b

rain/AUCplasm

aratio

was

26.1±12.1%

Unb

ound

cefotaximebrain

concen

trations

weremuchlower

than

correspo

ndingplasma

concen

trations

Simulated

brainconcen

trationat

two

dosage

regimen

s(usedfortreatm

ent

ofmen

ingitis)show

edT>MIC

high

erthan

90%

ofthedo

sing

intervalforbo

thdo

sing

regimen

s(4

gevery6hor

8h)

for

suscep

tiblestrainsandon

lyfor4gevery

6hforresistanton

es

Thereislim

itedbraindistrib

ution

ofcefotaxime

Highe

rcefotaximedo

sage

(4g6/6h)

isrequ

iredto

treatmen

ingitis

with

resistantbacterialstrains


Table

4PK/PDstud

iesof

beta-lactam

sin

cerebralspinalfluid

(Con

tinued)

Stud

yEndp

oints

Antibiotic

Design

Results

Con

clusions

Morita

etal.[154]

Toassess

theefficacy,safety,

andconcen

trationof

merop

enem

incerebrospinalfluid

Merop

enem

Observatio

nal,

prospe

ctivestud

y5adultICUpatients

with

men

ingitis

Merop

enem

2g8/h

(durationof

infusion

was

variablefro

m0.5to

2h)

CSF

andbloo

dwereob

tained

pre-treatm

entandon

days

3,7,

14,and

21

Con

centratio

nsin

cerebrospinalfluid

rang

edfro

m0.27

to6.40

μg/m

Lup

to8.47

handwereover

1μg

/mL3h

afterstartin

gmerop

enem

infusion

TheCSF/plasm

aconcen

trationratio

rang

edfro

m0.008to

0.013,0.011to

0.953,and0.633to

1.821,respectively,

with

in2h,2–6h,andafter6hfro

mthestartof

drug

infusion

Therelatio

nshipof

CSF

concen

tration

toCSF

cellcoun

ts,C

SF/plasm

aglucoseratio

,and

CSF

protein

concen

tration,respectively,was

statisticallycorrelated

with

CSF

cell

coun

tsandCSF

proteinconcen

tration,

andinverselycorrelated

with

CSF/

plasmaglucoseratio

Con

centratio

nof

merop

enem

inCSF

exceed

edtheminim

alinhibitory

concen

trationforthepathog

ens

involved

(pen

icillin

sensitive

S.pn

eumon

iaeandS.salivarius;methicillin-

sensitive

Staphaureus)

Noserio

usadverseeven

tandno

discon

tinuatio

nof

treatm

entoccurred

Themerop

enem

concen

trationin

the

CSF

canbe

expe

cted

tobe

high

becauseof

thepresen

ceof

inflammation

Tsum

ura

etal.[155]

Toexam

inePK

andPD

ofmerop

enem

incerebrospinal

fluid

Merop

enem

Observatio

nal,prospe

ctivestud

y6ne

urosurgicalp

atients

Merop

enem

(0.5gevery8h)

was

administereddu

ring0.5h.

LumbarCSF

andveno

usbloo

dsamples

wereob

tained

at0.5–16

hafterthestartof

thefirstinfusion

Pene

trationinto

theCSF

with

the

AUCratio

was

0.10

±0.03

(mean±SD

)Ado

sage

of0.5gq8

hachieved

a>90%

PTA(50%

oftheT>MIC),and1gq8

hwas

need

edfora>90%

PTA(100%

oft

heT>MIC)forsuscep

tibleisolates

ForP.aerugino

sa,2

gq8

hachieved

alower

PTA

Less

suscep

tiblebacterialC

NSinfections

may

notbe

optim

ized

with

standard

merop

enem

dosage

Nicasio

etal.[156]

Tode

scrib

etheuseandcerebral

spinalfluid

pene

trationof

aprolon

gedinfusion

merop

enem

regimen

inapatient

with

Serra

tiamarcescensmen

ingitis

Merop

enem

Caserepo

rtAdu

ltpatient

with

men

ingitis

and

epiduralabscess

Merop

enem

2gq8

h,3-hinfusion

Theprolon

ged(3

h)infusion

regimen

of2g8hresultedin

concen

trations

inbo

thserum

andCSF

abovethe

MIC

of0.047μg

/mL,for100%

ofthe

dosing

interval

CSF

pene

trationwas

6.4%

Theuseof

ahigh

-doseprolon

gedinfu-

sion

ofmerop

enem

resultedin

ad-

equate

expo

sure

atthesite

ofinfection

andasuccessful

clinicalrespon

seAtfollow-up,

thepatient

hadcompleted

a4-weekcourse

with

outrelapseor

ad-

verseeven

ts

Frasca

etal.[157]

Tode

scrib

ePK–PDprofile

ofcefotaximein

theCSF

Cefotaxim

eCaserepo

rtAdu

ltICUpatient

with

TBI

Cefotaxim

e4gq8

h,30-m

ininfusion

Microdialysiswas

perfo

rmed

onday4,

afterthe12th

dose

Unb

ound

plasmaCmax

was

118.8μg

/mL

CSF

Cmax

was

11.4μg

/mL

T>MIC

inthebrainwere,respectively,

78%

(6.2h)

and46%

(3.7h)

forMIC

values

of2and4μg

/mL

ECFbrainconcen

trations

indicate

that

anadeq

uate

expo

sure

tocefotaximeis

achieved

inpreven

tionandtreatm

ent

ofmostCNSinfections

with

the

standard

dosage

regimen

Wanget

al.[158]

Toexplorewhe

ther

thereisincreased

CSF

pene

trationof

cefope

razone

/sulbactam

whe

nthee

bloo

d–brain

barrierisim

pairedfollowingcraniotomy;

andwhe

ther

extend

edinfusion

time

affectsdrug

concen

trations

Cefop

erazon

e/sulbactam

Observatio

nal,prospe

ctivestud

yDosingwas

3.0gin

a3-hinfusion

every6h,aftercraniotomy

Veno

usbloo

dandCSF

werecollected

before

thestartof

drug

administration

andat

hour

1,2,3,4,6,12,15,16,

and18

afteradministration

8ne

urosurgicaladu

ltpatients

enrolled

CSF

pene

tration:

Peak

concen

trations

(CSF/serum

):8.6%

±7.2%

forcefope

razone

and

13.5%±11.9%

forsulbactam

Trou

ghconcen

trations

(CSF/serum

):13.4%±5.3%

forcefope

razone

and

106.5%

±87.5%

forsulbactam

Ratio

oftheAUCof

CSF

andserum:

14.5%

forcefope

razone

and22.6%

for

Ifcefope

razone

/sulbactam

sing

leinfusion

timeisextend

edto

3h,the

serum

drug

concen

trationachieved

the

PK/PDstandard

of>50%T>MIC

(MIC

90

64mg/L)

Itisvery

difficultto

achievethisPK/PD

standard

intheCSF,and

ahigh

erdo

semight

bene

eded

totreatintracranial

infections


Table

4PK/PDstud

iesof

beta-lactam

sin

cerebralspinalfluid

(Con

tinued)

Stud

yEndp

oints

Antibiotic

Design

Results

Con

clusions

sulbactam

Cefop

erazon

eserum

concen

trations

achieved

>50%T>MIC

forPseudomon

asandAcinetobacter(M

IC90

64mg/L)

and

100%

T>MIC

formoresuscep

tiblebacteria

CSF

cefope

razone

T>MIC%

was

almost100%

(Escherichia

coliMIC50)a

ndT>MIC%

was

morethan

50%

(Acinetobacterbaum

annii

MIC50)

Sulbactam

serum

concen

trations

achieved

>50%T>MIC

forAcinetobacter(M

IC90

16mg/L)

CSF

sulbactam

concen

trations

didno

treachthelevelo

fMIC

50of

8mg/L

forAcinetobacter

Destructio

nof

thebloo

d–brainbarrier

aftercraniotomycanincrease

theCSF

concen

trationto

acertainextent

AUCarea

unde

rthecurve,

CNScentraln

ervo

ussystem

,CRO

ceftria

xone

,CSF

cerebral

spinal

fluid,C

TXcefotaxime,

ICUintensivecare

unit,

MIC

minim

alinhibitory

concen

tration,

MIC50

minim

alinhibitory

concen

tration

for50

%of

isolates,P

TAprob

ability

oftarget

attainmen

t,SD

stan

dard

deviation,

T>MIC

percen

tage

oftim

eab

oveminim

alinhibitory

concen

tration,

TBItraum

abraininjury


beta-lactams [13, 20, 159]. The impact of infection ontheir penetration into ELF in humans is unknown [159],though some reports state that ELF penetration in-creases in acute lung injury [160].Only a few studies have investigated beta-lactam PK/PD

issues in critically ill patients with pneumonia (Table 5)and in only seven of them were ELF drug concentrationsmeasured. A standard dosage of beta-lactams derivedfrom healthy patients’ PK profiles may be insufficient fortreatment of critically ill patients with pneumonia, espe-cially when caused by multidrug-resistant pathogens. Con-tinuous or prolonged infusions and higher than standarddoses improve the PD profiles of these antibiotics. This isvery important to achieve an adequate PD profile whentreating less susceptible bacterial strains. Therapy drugmonitoring would be extremely helpful in this setting.

New beta-lactam drugs and beta-lactamasecombinationsOf great concern is the worldwide increase in the number ofinfections caused by Gram-negative multidrug-resistant bac-teria. Treatment choices for these infections have been lim-ited, especially for infections caused by bacteria that producecarbapenemases and/or extended-spectrum beta-lactamases.Ceftolozane–tazobactam and ceftazidime–avibac-

tam are 2 beta-lactams/beta-lactamase combinations withanti-Gram-negative bacteria activity that were recently ap-proved for the treatment of complicated intra-abdominalinfections, complicated urinary tract infections, and noso-comial pneumonia.Ceftolozane is an oxyimino-aminothiazolyl cephalo-

sporin with a pyrazole substituent at the 3-position sidechain instead of the lighter pyridium present in ceftazi-dime. This heavier side chain provides improved sterichindrance to prevent hydrolysis mediated throughAmpC beta-lactamases.Ceftolozane–tazobactam combines a novel cephalo-

sporin with an established beta-lactam beta-lactamaseinhibitor, whereas ceftazidime–avibactam couples awell-known cephalosporin with a novel non-beta-lactambeta-lactamase inhibitor.Both tazobactam and avibactam target the active site

of serine beta-lactamases. Tazobactam, a beta-lactamsulfone, binds irreversibly to the active site ofbeta-lactamases and avibactam is a diazabicyclooctanenon-beta-lactam that binds covalently and reversibly tobeta-lactamases. This reversibility is a unique featurethat allows avibactam to undergo recyclization to inacti-vate another beta-lactamase. The crucial advantage ofavibactam is its ability to inhibit extended spectrumbeta lactamases, AmpC beta-lactamases (as expressed inPseudomonas aeruginosa and Enterobacteriaceae), andclass A carbapenemases of the Klebsiella pneumoniaecarbapenemase (KPC and OXA-48) family.

The pharmacokinetic and safety profiles of this anti-biotic have been established in healthy adults and sub-jects with various degrees of renal function [170, 171].The currently approved dosages for adult patients withan estimated ClCr > 50 mL/minute are ceftolozane 1 gwith tazobactam 500 mg every 8 h and ceftazidime 2 gwith avibactam 500 mg every 8 h for complicated urin-ary tract infections and intra-abdominal infections [172]and ceftolozane 2 g with tazobactam 1 g every 8 h fornosocomial pneumonia [173].However, data guiding its use in critically ill patients

are currently sparse, being entirely derived from studieswith very few patients and/or case reports.Veillete et al. [174] presented PK data for ceftazidime–

avibactam from two patients with bloodstream infectionscaused by carbapenemase (KPC)-producing K. pneumo-niae; the patients had renal impairment and one of themwas obese. In both patients half-lives were prolongedand Vd larger than predicted. They conclude that rec-ommended doses and intervals may not be sufficient forobese patients with renal failure, especially for those in-fected with KPC-producing organisms [174].Oliver et al. [175] evaluated the adequacy of

extended-infusion ceftolozane–tazobactam to achievetarget PK and PD goals in a critically ill patient withPseudomonas aeruginosa pneumonia and septic shockon CVVH. A dosage of 1.5 g every 8 h (3-h infusion)was given. All estimated plasma-free drug concentra-tions achieved the PD goals and remained well abovethe isolated organism’s MIC of 1.5 μg/mL and above thesusceptibility breakpoint of 4 μg/mL throughout thedosing interval, although the authors could not com-ment on drug concentrations at the site of infection.The authors conclude that, given the lowest estimatedfree-drug concentration was fivefold greater than thesusceptibility breakpoint, the estimated half-life of 28 hand the low extraction ratio observed, a lower total dailydose might be utilized and an extended infusion timemay not be necessary for patients on CVVH [175].Bremmer et al. [176] performed a PK analysis of

intravenous ceftolozane–tazobactam 3 g every 8 h in acritically ill patient with P. aeruginosa pneumonia onCVVHDF. They concluded that, compared with a patientwith normal renal function, this patient had decreased cef-tolozane clearance. A ceftolozane–tazobactam dosage of1.5 g every 8 h should adequately achieve a desired drugconcentration above the minimum inhibitory concentra-tion of 8 μg/mL for the treatment of pneumonia [176].Stokem et al. reported the successful treatment with

ceftolozane–tazobactam 3 g every 12 h for a pulmonaryexacerbation in a 35-year-old female post-lung trans-plant, with cystic fibrosis, malnutrition, chronic kidneydisease, and multi-drug resistant P. aeruginosa infection.Optimal time above MIC (estimated 100% time above


Table

5PK/PDstud

iesof

beta-lactam

sin

bron

chial-alveo

larlavage

Stud

yEndp

oints

Antibiotic

Design

Results

Con

clusions

Kikuchi

etal.[52]

Com

pare

thePK/PDparameters

ofbiapen

emin

bron

chialELF

givenas

0.5-hand3-hinfusion

s

Biapen

emProspe

ctive,no

n-blinde

d,crossoverstud

y6he

althyadultvolunteers

Thepe

rcen

tage

(mean±SD

)of

T>MIC

inbron

chialELF

rang

edfro

mzero

(MIC

4μg

/mL)

to34.6%

±5.2%

(MIC

0.25

μg/m

L)afterthe0.5-hinfusion

and

from

5.1%

±5.6%

(MIC

4μg

/mL)

to52.2%±17.0%

(MIC

0.25

μg/m

L)after

the3-hinfusion

A3-hinfusion

ofbiapen

emtend

edto

prod

uceahigh

erT>MIC

inbron

chialELF,

aswellasin

plasma,than

a0.5-hinfusion

Theseresults

supp

orttheuseof

prolon

ged

infusion

sforsuccessful

treatm

entof

lower

respiratory

tractinfections

basedon

PK/PD

parametersin

bron

chialELF

Rodvold

etal.

[159]

Tode

finetheexpo

sure

targets

inlung

associated

with

good

microbiolog

icalactivity

ina

murinemod

elTo

determ

inedrug

pene

tration

into

ELFin

humans

Ceftobiprol

Prospe

ctive,ob

servationalstudy

Pre-clinical,m

urinemod

elClinicalstud

ywith

24he

althy

volunteers

500mgevery8h,2-h

infusion

regimen

Murinemod

el:for

cellkills

of1and2

log 1

0CFU

/g,totaldrug

mustbe

presen

tin

ELFat

aconcen

trationin

excess

ofthe

MIC

of12.9%

and24%

ofa24-h

interval,

respectively.ELFpe

netrationwas

69%

(med

ian)

MeanELFpe

netrationin

human

volunteerswas

25.5%

(med

ian,

15.3%;

interquartile

rang

e,7.9%

to30.4%)

Target

attainmen

tfalls

below

90%

for

acellkillof

2log 1

0CFU

/gat

aMIC

of1.0mg/Landfora1log 1

0CFU

/gcell

killat

aMIC

of2.0mg/L

Ceftobiprolepe

netrated

into

ELFvery

differentlyin

humanscomparedto

mice

Forserio

uslyillpatients,particularlyin

theICU,

high

erdo

sesor

long

erinfusion

times

(toprolon

gthetim

e>MIC),or

both,w

illbe

requ

iredto

comfortablyen

sure

a90%

target

attainmen

tfor

serio

uslyillpatientswith

MRSApn

eumon

ia

Con

teet

al.

Determinetheplasmaand

intrapulmon

aryELFandAC

pharmacokineticparametersof

intraven

ouslyadministered

merop

enem

Merop

enem

Prospe

ctive,ob

servational

Four

doses(8/8

h)of

0.5g,

1.0g

or2.0gwereadministered

intraven

ouslyto

20,20,and8

healthyadultsubjects,respe

ctively

Cmax,A

UC,T

1/2:

0.5ggrou

p:serum

25.8±5.8μg

/mL,

28.57μ

gh/mL,0.77

h;ELF5.3±2.5μg

/mL,

12.27μg

h/mL,1.51

h;AC1.0±0.5μ

g/mL,

4.30

μgh/mL,2.61

h1ggrou

p:serum

53.5±19.7μg

/mL,

55.49μ

gh/mL,1.31

h;ELF7.7±3.1μ

g/m

L,15.34μg

h/mL,0.95

h;AC5.0±3.4μg

/mL,

14.07μg

h/mL,2.17

h2ggrou

p:serum

131.7±18.2μg

/mL,

156.7μg

h/mL,0.89

hT≥MIC

(MIC90

values

of0.12–4μg

/mL):

0.5ggrou

p:serum

28–78%

,ELF

18–100%,

AC0–100%

1gGroup

:serum

45–100%,ELF

25–88%

,AC24–100%

Theprolon

gedT>MIC90

andhigh

intrapulmon

arydrug

concen

trations

following

every8hadministrationof

0.5–2.0gdo

sesof

merop

enem

arefavorableforthetreatm

entof

common

respiratory

pathog

ens.

Boselli

etal.

[161]

Determinethesteady-state

serum

andalveolar

concen

trations

ofpipe

racillin/tazobactam

administeredin

continuo

usinfusion

(12/1.5g/dayor

16/2

g/day)

atvario

usde

greesof

renal

failure

(terminalrenalfailure

exclud

ed)

Pipe

racilin/

tazobactam

Prospe

ctive,op

en-labe

l,comparative,sing

lecenter

40ICUpatientswith

ventilator-associated

pneumon

iaSamples

collected

after2days

oftreatm

ent

Med

ian(interquartile)serum

andalveolar

pipe

racilin

concen

trations

No/mild

renalfailure

(creatinineclearance

≥50

mL/min)

Serum

25.3mg/L(23.1–32.6)andalveolar

12.7mg/L(6.7–18.0)

for12/1.5g/day

Serum


19.1mg/L(14.0–21.5)for16/2

g/day

Mod

erate/advanced

renalfailure

(creatinineclearance<50

mL/min)

Serum

102.4mg/L(97.4–112.6)

and

alveolar

44.1mg/L(33.4–48.3)for12/2

g/day

Serum


54.9mg/L(45.2–110.3)

for16/2

g/day

Alveo

larpe

netrationwas

40–50%

for

pipe

racillinand65–85%

fortazobactam

Therewas

apo

sitivelinearrelatio

nship

betw

eenELFandserum

concen

trationin

both

patientsreceiving12/1.5g/day

Theadministrationof

daily

continuo

usinfusion

sof

P/T12/1.5gor

even

16/2

gmight

provideinsufficien

talveolar

concen

trationto

eradicatehigh

-riskpathog

ens

with

high

MICssuch

asmulti-drug

resistantP.aerugino

sain

patientswith

noor

mild

renalinsufficiency

Alinearrelatio

nshipbe

tweenalveolar

andserum

pipe

racillinconcen

trationwas

observed

inthisstud

y,with

ELFpipe

racillinconcen

trationbe

ing40–50%

ofcorrespo

ndingserum

values


Table

5PK/PDstud

iesof

beta-lactam

sin

bron

chial-alveo

larlavage

(Con

tinued)

Stud

yEndp

oints

Antibiotic

Design

Results

Con

clusions

(r=0.8437,P

<0.0001)and16/2

g/day

(r=0.7935,P

<0.0001)

T>MIC

was

100%

(assum

ingMIC

>16

mg/L)

inbo

thserum

andELFin

allp

atientswith

mod

erate/advanced

renalfailure;inpatients

with

no/m

ildrenalfailure

thisthresholdwas

notreache

din

6patientswith

12/0.5gdo

sing

and4patientswith

16/2

gdo

sing

Cou

sson

etal.

[162]

Com

pare

continuo

usvs

interm

itten

tadministrationof

drug

Determineaverageconcen

tration

inELF

Determinethefractionof

time,

durin

gthefirst48

hof

treatm

ent,

whe

reserum

concen

trations

remaine

dabovethe20

mg/Lplasmathreshold

Ceftazidime

Sing

le-cen

ter,controlled,

rand

omized

trialintw

oparallelg

roup

scomparin

gtw

omod

esof

administration:

grou

pA,

loadingdo

se20

mg/kg

+60

mg/kg/day;

grou

pB,20

mg/kg

over

30min

every8h


ventilator-

associated

pneumon

iadu

eto

Gram-neg

ativebacilli.

ThemeanMIC

ofceftazidim

efor

P.aerugino

sawas

estim

ated

at2mg/L.

Thetarget

thresholdvaluefor

ceftazidim

ein

theELFwas

thus

fixed

at8mg/L,with

acorrespo

nding

serum

thresholdof

20mg/L

PlasmaT>20

mgwas

100%

ingrou

pAversus

46%

ingrou

pB(P<0.003)

IntheELF,themed

ianconcen

trationwas

12mg/Lin

grou

pAversus

6mg/Lin

grou

pB(P<0.08)

Athresholdof

8mg/Lin

theep

itheliallining

fluid

was

achieved

twiceas

oftenin

grou

pAas

ingrou

pB

Con

tinuo

usinfusion

presen

tsadvantages

interm

sof

PDandpred

ictableefficacyin

patientspresen

ting


pneumon

ia

Burkhardt

etal.

[163]

Determinein

vivo

pene

trationinto

LT,ELF,and

ACafter1gof

ertape

nem

(infusion

perio

d30

min)for

perio

perativeprop

hylaxis

Ertape

nem

Sing

le-cen

ter,prospe

ctive,

observational

of15

patientsun

dergoing

thoracotom

yBA

Lpe

rform

edat

1,3,and

5hafterertape

nem

infusion

Plasmaconcen

trationcollected

upto

24hafterinfusion

LTcollected

attim

eof

lung

extractio

n

Meanconcen

trations

inplasma,ELF,andAC

were:at

1.0h,

63.1,4.06,0.004mg/L;at

3.0h,

39.7,2.59,0.003mg/L;at

5.0h,27.2,2.83,0.007mg/L

Mean(rang

e)concen

trationin

LTwas

7.60

(2.5–19.4)

mg/kg

tissue,1.5to

4.5hafterinfusion

andLT

plasmaconcen

trationratio

was

23.6±12.3%

Meanlevelo

fELFpe

netrationwas

7.48%±8.17%,

andthehigh

estde

gree

ofpe

netrationwas

recorded

at5hafterinfusion

(mean±SD

,9.40%±10.7%)

A1-gdo

se,oncedaily,resultsin

drug

plasma

concen

trations

high

erthan

MICsof

mostcommun

ity-acquired

respiratory

pathog

ensdu

ringtheen

tiredo

sing

interval

Meanconcen

trations

inELFexceed

edMIC90

values

ofhigh

lyor

mod

eratelype

nicillin-sensitive

Pneumococci

andof

H.

influenzaewith

in1to

5hafterstartof

infusion

and

werepartlybe

low

theMIC90

ofpe

nicillin-resistant

Pneumococci

Theseresults,com

bine

dwith

therepo

rted

MIC

90

ofmostCAPbacteria,sup

portthepreviouslyob

served

clinicalefficacyof

ertape

nem

inthetreatm

entof

commun

ity-acquiredpn

eumon

ia

Boselliet

al.[164]

Determinethesteady-state

serum

andELFconcen

trations

ofun

boun

dertape

nem

administeredon

cedaily

tocritically

illpatientswith

early-onset


pneumon

ia

Ertape

nem

Prospe

ctive,op

en-labe

lstudy

inan

intensivecare

unit

15patientswith

VAPreceived

1-h

intraven

ousinfusion

sof

1gertape

nem

once

daily

Samples

obtained

atsteady-state,

after2days

oftherapy

ELFob

tained

bymini-BAL

Med

ian(interquartile

rang

e)Cmax,C

12,and

Cmin

concen

trations

(mg/l)1,12,and

24haftertheen

dof

infusion

were:30.3(27.1–37.8),4.8(3.9–6.4),and

0.8(0.5–1.2)

inserum

and9.4(8.0–10.7),2.0(1.1–2.5),

and0.3(0.2–0.4)in

ELF,respectively

Med

ianfre

epe

rcen

tage

pene

trationin

ELF

approxim

ately30–40%

Con

centratio

nsexceed

ingtheMIC90

values

ofmostof

thecausativepathog

ens(0.25–2mg/lfor

S.pn

eumon

iae,

0.06–0.125

mg/lfor

Haemophilusinfluenzae,0.25–0.5mg/l

foroxacillin-susceptible

S.aureus,and

0.03–0.125

mg/l

forEnterobacteriaceae

andanaerobe

s0.5–1mg/lw

asen

coun

teredin

early-onset

VAPdu

ring50–100%

time

1gintraven

ousertape

nem

once

daily

shou

ldbe

effectiveforearly-onset

VAPICUpatientswith

noknow

nriskfactorsfor

multid

rug-resistantpathog

ens


Table

5PK/PDstud

iesof

beta-lactam

sin

bron

chial-alveo

larlavage

(Con

tinued)

Stud

yEndp

oints

Antibiotic

Design

Results

Con

clusions

Boselliet

al.[165]

Tode

term

inethesteady-state

plasma

andELFconcen

trations

ofceftazidim

eadministeredin

continuo

usinfusion

tocritically

illpatients

with

severe

nosocomialp

neum

onia

Ceftazidime

Prospe

ctive,op

en-labe

lstudy.

15adultpatientswith

severe

nosocomial

bacterialp

neum

oniaon

mechanical

ventilatio

nAdm

inistrationof

30min

infusion

of2g

ceftazidim

efollowed

bycontinuo

usinfusion

4gover

24h

Bloo

dandmini-BALsamples

collected

bythethird

dayof

antib

iotic

therapy

(8:00am

,12:00

pm,and

6:00

pm)

Themean±SD

steady-state

plasmaand

ELFconcen

trations

incontinuo

usinfusion

were39.6±15.2g/mLand8.2±4.8g/mL,

respectively,show

ingamean±SD

percen

tage

pene

trationof

ceftazidim

einto

ELFof

20.6±8.9%

Theadministrationof

theapplieddo

sein

critically

illpatientswith

severe

nosocomialp

neum

oniaprovides

concen

trations

inexcess

oftheMIC

ofmanysuscep

tible

organism

sover

thecourse

oftherapyin

both

serum

andELF.How

ever,for

somepathog

enssuch

asP.aerugino

sa,h

ighe

rdo

sesof

ceftazidim

eshou

ldbe

administered,

oranothe

ragen

tshou

ldbe

used

incombinatio

n

Felto

net

al.[166]

Toassess

plasmaandintra-pu

lmon

ary

PKof

pipe

racillin/tazobactam

incritic-

allyillpatients

Quantify

pulm

onarype

netration

Iden

tifyfactorsthat

may

influen

cepu

lmon

arype

netration

Pipe

racilin/

tazobactam

Prospe

ctive,op

enlabe

l,sing

learm

stud

y18

ICUadultpatientswith

pneumon

iaAdm

inistrationof

4/0.5ginfusion

every

8hdaily

Samples

collected

atsteady-state

(mean

of8.8do

ses(rang

e2–16).

Non

-directed

bron

chiallavagewas

perfo

rmed

forELFsampling

Med

ianpipe

racilin

andtazobactam

pulm

onarype

netrationratio

was

49.3%

and121.2%

respectively.

ELFprotein/plasmaproteinratio

,asa

surrog

atemeasure

oflung

perm

eability,

was

foun

dto

have

astatisticallyne

gative

correlationbe

tweenpipe

racilin

pulm

onary

pene

trationratio

andpu

lmon

arype

rmeability.

Therewas

nostatisticallysign

ificant

correlationfortazobactam

14–18%

ofpatientswillhave

subo

ptim

aldrug

expo

sure

(ELF

50%T>MIC)whe

ninfected

with

a“susceptible”(M

IC<16

mg/L)

organism

Pipe

racilin

andtazobactam

plasmaconcen

trations

dono

tpreciselypred

ictELFconcen

trations

ofbo

thdrug

s

Current

pipe

racilin-tazob

actam

regimen

sisinadeq

uate

foreffectivetreatm

entandsupp

ressionof

emerge

nce

ofantim

icrobialresistance

inan

unacceptablyhigh

prop

ortio

nof

critically

illpatients,espe

ciallythosewith

pneumon

iaresulting

from

infectionwith

aless

suscep

tible

organism

Boselliet

al.[167]

Tode

term

inethesteady-state

plasma

andELFconcen

trations

ofcefepime

administeredin

continuo

usinfusion

incritically

illpatientswith

severe

bacterialp

neum

onia

Cefep

ime

Prospe

ctive,op

en-labe

lstudy

20ICUadultpatientswith

severe

nosocomialb

acterialp

neum

onia

Allsubjectsreceived

a30-m

inintraven

-ou

sinfusion

ofcefepime2gfollowed

byacontinuo

usinfusion

of4gover

24h

Samples

werecollected

after48

hof

therapy.Bloo

dandminiB

ALsamples

werecollected

at8:00

am,12:00

pm,and

6:00

pm

Mean±SD

steady-state

plasmaandELF

concen

trations

were13.5±3.3g/mLand

14.1±2.8g/mL,respectively,with

amean

percen

tage

pene

trationinto

epith

eliallining

fluid

ofabou

t100%

Adm

inistrationof

cefepimein

continuo

usinfusion

incritically

illpatientswith

severe

nosocomialp

neum

onia

appe

arsto

optim

izetheph

armacod

ynam

icprofile

ofthis

beta-lactam

byconstantlyprovidingconcen

trations

inexcess

ofMIC

ofmostof

thesuscep

tibleorganism

sover

the

course

oftherapyin

both

serum

andELF

Forsomepathog

enssuch

asAcinetobacterspp.

and

P.aerugino

sahigh

erdo

sesshou

ldbe

administered

Boselliet

al.[168]

Tode

term

inethesteady-state

plasma

andep

ithelialliningfluid

concen

tra-

tions

ofpipe

racillin/tazobactam

admin-

isteredto

critically

illpatientswith

severe

bacterialp

neum

onia

Pipe

racilin/

tazobactam

Prospe

ctive,op

enlabe

lstudy

10ICUadultpatientswith

severe

nosocomialp

neum

onia

30-m

inintraven

ousinfusion

4/0.5gevery

8h

Samples

wereob

tained

atsteady-state,

after2days

oftreatm

ent.Bloo

dsamples

werecollected

atthree

pred

etermined

timepo

intsat

7:00

am(troug

h),8:00am

(peak),and

12:00pm

(interm

ediate)

MiniB

ALwas

perfo

rmed

simultane

ously

tobloo

dsamplingat

12:00pm

Mean±SD

steady-state

plasmatrou

gh,p

eak,

andinterm

ediate

concen

trations

were

8.5±4.6μg

/mL,55.9±21.6μg

/mL,and

24.0±13.8μg

/mLforpipe

racillin,

and

2.1±1.0μg

/mL,4.8±2.1μg

/mL,and

2.4±1.2μg

/mLfortazobactam

Mean±SD

steady-state

interm

ediate

ELFconcen

trations

were13.6±9.4μg

/mL

forpipe

racillinand2.1±1.1μg

/mLfor

tazobactam

,respe

ctively

Meanpe

rcen

tage

pene

tration

ofpipe

racillinand

tazobactam

into

ELFwas

56.8%

and

91.3%,respe

ctively

Treatm

entof

severe

nosocomialp

neum

oniawith

aregimen

ofP/T4/0.5gevery8hmight

provide

insufficien

tconcen

trations

into

lung

tissueto

exceed

theMIC

ofmanycausativepathog

ens


Table

5PK/PDstud

iesof

beta-lactam

sin

bron

chial-alveo

larlavage

(Con

tinued)

Stud

yEndp

oints

Antibiotic

Design

Results

Con

clusions

Lodise

etal.[169]

Tode

scrib

ethePD

profile

ofcefdito

renin

plasmaandELF

Cefditoren

Ope

n,no

ncon

trolled,

dual-cen

ter,ph

aseIstudy

24adultpatientswith

sche

duled

bron

choscopy

Sing

leoraldo

se400mgcefdito

ren

Threesamplingtim

ewindo

ws(1–2

h,2–

3h,

or3–4hpo

st-adm

inistration)

Plasma/ELFconcen

trations

(mg/L)/pen

etratio

nratio

s1–2h:

1.78

±1.27/0.39±0.21/38.1±50.1%

2–3h:

1.33

±0.95/0.34±0.25/23.2±18.1%

3–4h:

1.03

±0.51/0.30±0.18/31.8±19.2%

AUC

ELF/AUC

plasm

ape

netrationratio

(mean±SD

)was

0.33

±0.48

PTAin

plasmafT>MIC

of60

to70%

was

<90%

forMICsof

>0.03

mg/L

PTAin

ELFT>MIC

of60%

and70%

were

90.26%

and86.65%

,respe

ctively,at

aMIC

of0.0125

mg/Landweresign

ificantlyless

forhigh

erMICs

Cefditorenpe

netrates

reason

ablywellintotheELF,

asde

fined

bythemeanAUCELF/AUCplasm

a

pene

trationratio

Theoverallp

robabilityof

target

attainmen

t(T>MIC

>50%)in

plasmaandELF,ho

wever,

was

subo

ptim

al(<

90%)

ACalveolar

cells,A

UCarea

unde

rthecurve,

BALbron

choa

lveo

larlavage

,CAPcommun

ity-acq

uiredpn

eumon

ia,C

maxmaxim

alconcen

tration,

C 12concen

trationat

12h,

Cmintrou

ghconcen

tration,

CFUcolony

form

ing

unit,

ELFep

ithelialliningflu

id,ICU

intensivecare

unit,

LTlung

tissue,

MIC

minim

alinhibitory

concen

tration,

MIC90

minim

alinhibitory

concen

trationfor90

%of

isolates,M

RSAmethicillin-resistan

tStap

hylococcus

aureus,

P/Tpipe

racillin/tazoba

ctam

,PTA

prob

ability

oftarget

attainmen

t,SD

stan

dard

deviation,

T 1/2ha

lf-life,

T>MIC

percen

tage

oftim

eab

oveminim

alinhibitory

concen

tration,

VAPventilator-associated

pneu

mon

ia


MIC of ceftolozane achieved against both isolates was 2and 0.5 μg/mL) was likely attained at the dose and fre-quency provided in this case [177].

ToxicityBeta-lactams are generally considered to have a high safetywindow with relatively few adverse effects, even whenhigh doses are used [15]. Neurotoxicity is the most re-ported serious adverse effect of beta-lactams. Benzylpeni-cillin, cefepime, ceftazidime, and imipenem are consideredto be the high-risk beta-lactams for neurotoxicity. Renalimpairment, excess doses and/or concentrations, age, anda prior history of neurological disorders are known to bepredisposing factors [2, 178–184].Other adverse effects are found in a few case reports:

acute renal failure [185] and electrolyte disorders [186];severe intravascular haemolysis [187, 188]; extremethrombocytosis [189]; severe thrombocytopenia [190–193]; leukopenia [194]; delayed-type hypersensitivity[195]; anaphylactic shock [196]; and severe cutaneous re-actions [197].

Therapeutic dose monitoringSeveral studies reported high PK variability ofbeta-lactams in sepsis/septic shock, both in different pa-tients and in the same patient over time. In critically illpatients, hydrophilic and moderately lipophilic antimi-crobials, being at higher risk of daily PK variations,should be more closely monitored and their dosagesshould be streamlined according to the underlying dis-eases in order to prevent under- or overexposure [2, 11].Therapeutic drug monitoring (TDM) has been insti-

tuted for aminoglycosides and glycopeptides to reduce therate of toxicity. However, because of the safety profile ofbeta-lactams, TDM was thought unnecessary for thesedrugs. In line with PK changes in critically ill patients, in-sufficient PD target attainment with beta-lactams has beenreported in these patients, especially those with hypoalbu-minemia, altered renal function, and low susceptibilitybacterial strain infections [2, 35, 42, 198]. The challengesin achieving ‘optimal’ drug concentrations in the criticallyill suggest beta-lactam TDM as a useful strategy tooptimize drug exposure [199].The TDM approach could be particularly useful in

a certain group of critically ill patients in whomachieving target concentrations is more difficult, suchas those with highly resistant bacterial strains, obesepatients, immunocompromised patients, those under-going renal-replacement therapies, and patients withaugmented renal clearance [2, 198, 200, 201].Though there are PK models to estimate antibiotic

concentrations over a range of creatinine clearance(CrCl) and on renal replacement therapy [67, 202–205],the use of CrCl as a tool to optimize beta-lactam dosing

may not be reliable; although CrCl was significantly corre-lated with concentrations and clearance of broad-spectrumbeta-lactams, changes in CrCl and RRT parameters do notreliably predict variations in drug PK/PD. In this setting,routine TDM should be considered to adapt beta-lactamdoses [206].Daily TDM of beta-lactams with dose adaptation in

critically ill patients improves PD target attainment[207, 208]. Case reports have shown that TDM improvedclinical outcome [209], but the clinical efficacy of usingdrug levels to achieve adequate concentrations had neverbeen properly evaluated [1, 35, 210, 211] and there are re-ports concerning cost-effectiveness [111].Facing poor implementation in beta-lactam TDM,

Delattre et al. [212] proposed a predictive PK perform-ance between an aminoglycoside and a beta-lactam. Dueto physicochemical and PK similarities between amino-glycosides and beta-lactams, optimization of thebeta-lactam dosage could be reached without anybeta-lactam measurements, using TDM-related data ofan aminoglycoside. The study aimed to characterize thePK of four beta-lactams (piperacillin, ceftazidime, cefe-pime, and meropenem) at the first dose in 88 criticallyill septic patients co-medicated with amikacin, and toconfirm the predictive performance of amikacin data onthese PK, on a larger patient cohort, using a nonlinearmixed-effects modeling approach. There was a signifi-cant relationship between the exposure to amikacin andto beta-lactams. The population model presented wasable to guide dosage adjustments for piperacillin, ceftazi-dime, cefepime, and meropenem during the early phaseof severe sepsis in critically ill patients, using renal bio-markers or TDM-related aminoglycoside data [212].

ConclusionsThe duration of infusion of beta-lactams has beenshown to influence their fT >MIC and an improved PDprofile of beta-lactams may be obtained by longer expos-ure with more frequent dosing, extended infusions, orcontinuous infusions. This is particularly relevant in thecritically ill patient, as Vd and ClCr are often increased,namely in the early phase of systemic hyperinflammatorystates, promoting the risk of antibiotic underdosing.The use of extracorporeal support techniques, either

for renal replacement or ECMO, may further contributeto this problem and consequently concentrations belowthose expected are often found for beta-lactams. Giventhe heterogeneity of extracorporeal support therapymodes, it is difficult to suggest a specific dosage, but werecommend not to reduce dosage since no drug accu-mulation was found in the available literature and to usecontinuous or prolonged infusions to achieve the ad-equate PD profiles necessary to successfully treat infec-tions caused by less susceptible strains.


More studies are needed to define optimal dosing ofnew beta-lactams and new beta-lactam/beta-lactamasecombinations, which are increasingly important to ef-fectively treat multidrug-resistant bacterial strains,namely in patients on extracorporeal support therapyand with difficult-to-treat sites of infection.Although, it is not currently a clinical routine in most

hospitals and its clinical efficacy has not yet been prop-erly evaluated, a beta-lactam TDM approach with dailydose adaptation, allowing personalized antibiotic dosing,should be particularly useful in critically ill patients inwhom achieving target concentrations is more difficult,such as obese patients, the immunocompromised, pa-tients with augmented renal clearance, those undergoingextracorporeal support therapy, or those infected withhighly resistant bacterial strains. Studies comparingTDM- versus non-TDM-based beta-lactam regimensshould be promoted.However, infection usually occurs at extravascular sites

and prediction of outcome based on antibiotic plasmaconcentrations may result in overestimation of antimicro-bial activity at the site of infection. Very few studies haveinvestigated PK/PD issues concerning special anatomicbarriers like the brain and lung, but most suggest thatstandard ICU dosing for beta-lactams may be insufficientfor low susceptibility/high MIC pathogens in these sites.Therefore, although no studies have assessed clinical out-come, we recommend using higher than standard dosing,preferably with continuous or prolonged infusions, whentreating severe infections caused by less susceptible bac-terial strains at these sites, as PD profiles may improveand toxicity does not seems to increase.

AbbreviationsAKI: Aacute kidney injury; AUC: Aarea under the curve; C: Concentration;CFU: Colony-forming units; CI: Continuous infusion; Cl: Clearance;ClCr: Creatinine clearance; CNS: Central nervous system; CRRT: Continuousrenal replacement therapy; CSF: Cerebral spinal fluid; CVVHD: Continuousvenous-venous hemodialysis; CVVHDF: Continuous venous-venous hemodia-filtration; CVVHF: Continuous venous-venous hemofiltration;ECMO: Extracorporeal membrane oxygenation; EDD: Extended daily dialysis;ELF: Epithelial lining fluid; ICU: Intensive care unit; II: Intermittent infusion;KPC: Carbapenemase producing Klebsiella; MBC: Minimal bactericidalconcentration; MIC: Minimum inhibitory concentration; PAE: Post-antibioticeffect; PD: Pharmacodynamics; PK: Pharmacokinetics; PTA: Probability oftarget attainment; RRT: Renal replacement therapy; SLED: Sustained low-efficiency dialysis; TDM: Therapeutic drug monitoring; VAP: Ventilatorassociated pneumonia; Vd: Volume of distribution

Availability of data and materialsAll data generated or analyzed during this study are included in thispublished article (see bibliography).

Authors’ contributionsRV and JAP made substantial contributions to conception and design,acquisition of data, and analysis and interpretation of data; were involved indrafting the manuscript or revising it critically for important intellectualcontent; gave final approval of the version to be published; agreed to beaccountable for all aspects of the work in ensuring that questions related tothe accuracy or integrity of any part of the work are appropriatelyinvestigated and resolved.

Ethics approval and consent to participateNot applicable.

Consent for publicationNot applicable.

Competing interestsThe authors declare that they have no competing interests.

Publisher’s NoteSpringer Nature remains neutral with regard to jurisdictional claims inpublished maps and institutional affiliations.

Author details1Centro Hospitalar São João, EPE – Intensive Care Department, Porto,Portugal. 2Faculty of Medicine – University of Porto, Porto, Portugal. 3GrupoInfeção e Sepsis, Porto, Portugal.

Received: 23 April 2018 Accepted: 8 August 2018

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Pharmacokinetics–pharmacodynamics issues relevant for the ......REVIEW Open Access Pharmacokinetics–pharmacodynamics issues relevant for the clinical use of beta-lactam antibiotics