Pharmacokinetics of Meropenem in Burn Patients with Infections Caused by Gram Negative Bacteria: Are We Getting Close to the Right Treatment?

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Pharmacokinetics

of

meropenem

in

burn

patients

with

infections

caused

by

Gram-negative

bacteria:

Are

we

getting

close

to

the

right

treatment?

Silvia

Corcione

a,

*,

Antonio

D

_’Avolio

b

,

Riccardo

Corgiat

Loia

a

,

Anna

Pensa

c

,

Francesco

Vladimiro

Segala

a

,

Amedeo

De

Nicolò

b

,

Giovanna

Fatiguso

b

,

Mariarosa

Romeo

c

,

Giovanni

Di

Perri

a

,

Maurizio

Stella

c

,

Francesco

Giuseppe

De

Rosa

a

DepartmentofMedicalSciences,InfectiousDiseases,UniversityofTurin,Turin,Italy

b

DepartmentofMedicalSciences,UniversityofTurin–ASL‘CittàdiTorino’,LaboratoryofClinicalPharmacologyandPharmacogenetics,AmedeodiSavoia Hospital,Turin,Italy

c

BurnCenter,CTOHospital,CittàdellaSaluteedellaScienza,Turin,Italy

ARTICLE INFO Articlehistory: Received3October2018

Receivedinrevisedform4June2019 Accepted10June2019

Availableonline14June2019 Keywords: Burn Meropenem Pharmacokinetics Pharmacodynamics Multidrug-resistant Infection ABSTRACT

Objectives:Infectionscausedbymultidrug-resistantGram-negativebacteriaareassociatedwithhigh mortality. A relevant concern is the efﬁcacy of antibiotic therapy in burn patients in whom pathophysiologicalchangesstronglyinﬂuencepharmacokinetic(PK)parameters.Thisstudyaimedto describethePKparametersofmeropeneminapopulationofburnpatients.

Methods:Bloodsampleswerecollectedimmediatelybeforeand2hand5hafterthestartofintravenous drugadministration.Plasmameropenemconcentrationsweredeterminedusinganultra-performance liquidchromatography–photodiodearraymethod.

Results:Seventeenburnpatientswereenrolledinthestudy.Thirteenpatients(76%)weretreatedwith meropenemforinfectionsbyPseudomonasaeruginosaorAcinetobacterbaumanniiisolatedfrombloodor wounds.MeanCmax,Cmin,AUC0–24,half-life,drugclearanceandvolumeofdistributionwere28.9mg/L,

3.7mg/L,280.2mgh/L,2.0h,19.0L/hand44.4L,respectively.Sixpatients(35%)achievedaCmin3.3mg/

Landsevenpatients(41%)achievedaCmax28.4mg/L,whilstninepatients(53%)achievedanAUC0–24of

>226mgh/L.Givenaminimuminhibitoryconcentration(MIC)of0.5mg/L,allpatientssatisﬁedthe targetAUC/MICof>125,butwhentheMICrisesto2mg/L(theECOFF),onlyﬁvepatientsreachedthe desiredAUC/MIC.RegardingfT>MICatanMICof2mg/Lwitha2-hinfusiontime,13patients(76%)

achievedthePKtarget(>75%).

Conclusion:Thesedata suggestthatacombined2-hinfusionwithahigherdosageofmeropenem, includingaloadingdose,maybesuccessfultoachieveeffectivePKparameters.

1.Introduction

Despite improvements in the early care of burn patients, infectionsremainoneofthemajorcausesofmortality,responsible for46–51%ofmultiorganfailuretriggers[1].Inrecentyears,the emergence of infections caused by multidrug-resistant (MDR) Gram-negativebacteria,suchasPseudomonasaeruginosa, Acine-tobacterbaumanniiandKlebsiellapneumoniae,representsaglobal

threat,alsointhesettingofburnpatients[1].Alongwiththehigh mortality rate associated with these infections, an important concernistheefﬁcacyofantibiotictreatment,especiallyforburn patientsinwhompathophysiologicalchangesstronglyinﬂuence thepharmacokinetic(PK)parametersofmanyantibiotics[1–5].

Physiologicalchangesinburnpatientsaretime-dependentand a number of factors, such as the areaand depth of the burn, presence of sepsis,degree of hydration,serum protein concen-trations,age,creatinineclearanceandtimeafterinjury,mayaffect pharmacokineticsinburnpatients[1–5].Infact,majorchangesin ﬂuidvolumemayincreasethevolumeofdistributionofa drug therebyloweringitsconcentrationwhenastandarddoseisgiven.

*Correspondingauthor.

E-mailaddress:[email protected](S.Corcione). https://doi.org/10.1016/j.jgar.2019.06.011

ContentslistsavailableatScienceDirect

Journal

of

Global

Antimicrobial

Resistance

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Clinical and pharmacokinetic parameters of burn patients treated with meropenem. Pt. ID Age

(years)

Sex BMI Degree of burn % TBSA RBS CCI Reconstructive operations (n) MELD score CLCr (mL/ min) CRRT MV Septic shock Possible drug–drug interactions In-hospital mortality Cmax (mg/L) Cmin (mg/L) AUCss (mg h/L) AUC0–24 (mg h/L) t1/2 (h) CLss (L/h) Vd (L) Dose 1 71 M 29 2 50 143 5 Y (1) 8 86 N Y N None N 14.3 2.4 91.3 182.6 3.8 10.9 60.3 1 g b. i.d. 2 40 M 22 2 40 97 0 Y (3) 9 247 N N N None N 11.3 0.0 25.7 77.1 0.4 38.9 25.0 1 g t. i.d. 3 25 M 22 2 50 92 0 Y (5) 12 252 N Y N None N 17.1 3.1 61.7 185.1 2.4 32.4 112.9 2 g t. i.d. 4 43 M 29 2 55 115 0 Y (5) 15 64 Y Y Y Norepinephrine N 16.9 3.3 45.3 181.2 1.9 35.6 70.2 1 g q. i.d. 5 25 M 23 2 50 92 0 Y (4) 10 277 N N N None N 29.2 0.7 78.1 234.3 1.1 25.6 41.3 2 g t. i.d. 6 71 F 22 1 10 81 3 N 9 58 N N N None N 25.1 1.7 78.9 236.7 1.5 12.6 28.3 1 g t. i.d. 7 81 M 27 2 40 138 4 Y (5) 10 211 N N Y Furosemide and norepinephrine N 31.1 0.8 81.2 243.6 1.1 24.6 41.0 2 g t. i.d. 8 50 M 24 2 35 102 1 Y (1) 9 167 N N N None N 15.1 1.1 50.0 150 1.5 19.9 45.8 1 g t. i.d. 9 72 M 25 2 15 87 3 Y (1) 9 85 N N N None N 35.6 0.0 75.8 227.4 0.3 13.1 7.5 1 g t. i.d. 10 67 M 25 2 30 114 2 Y (6) 9 169 N Y N None N 20.8 3.6 67.5 202.5 2.3 14.8 50.5 1 g t. i.d. 11 52 F 37 2 50 119 5 Y (4) 9 98 N Y N Furosemide and norepinephrine Y 26.0 8.4 121.7 365.1 3.7 8.2 43.8 1 g t. i.d. 12 75 M 17 2 5 80 4 Y (2) 7 64 N Y N None N 36.5 6.7 158.3 474.9 2.4 6.3 22.4 1 g t. i.d. 13 48 F 19 2 18 66 0 Y (2) 8 82 N N N None N 74.7 0.0 151.0 453 0.3 6.6 10.4 1 g t. i.d. 14 40 F 23 2 35 75 0 Y (1) 11 150 N N N Furosemide N 16.0 0.6 36.0 108 1.2 27.7 20.1 1 g t. i.d. 15 70 M 27 2 35 122 5 Y (1) 9 76 N Y Y Furosemide and norepinephrine Y 50.2 21.4 262.1 786.3 4.8 7.6 53.6 1 g t. i.d. 16 64 M 27 2 45 127 2 Y (2) 20 31.7 N Y N Furosemide N 52.0 6.9 230.1 460.2 3.3 6.7 33.2 1 g b. i.d. 17 80 M 30 1 10 107 7 Y (1) 8 157 N Y N Furosemide N 19.9 2.5 64.9 194.7 1.9 30.8 88.2 2 g t. i.d. Pt., patient; M, male; F, female; BMI, body mass index; TBSA, total body surface area; RBS, revised Baux score; CCI, Charlson comorbidity index; Y, yes; N, no; MELD, Model for End-Stage Liver Disease; CLCr, creatinine clearance; CRRT,

continuous renal replacement therapy; MV, mechanical ventilation; Cmax, peak serum concentration; Cmin, trough serum concentration; AUCss, area under the concentration–time curve at steady-state; AUC0–24, area under the

concentration–time curve from 0–24 h; t1/2, half-life; CLss, drug clearance at steady-state; Vd, volume of distribution; b.i.d., twice daily; t.i.d., three times a day; q.i.d., four times a day.

S. Corcione et al. / Journal of Global Antimicrobial Resistance 20 (2020) 22 – 27 23

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Inaddition,augmentedrenalbloodﬂowinburnpatientsowingto theincreaseincardiacoutputmayresultinhigherdrugclearance andashortereliminationhalf-life[6,7].

AlteredPKparametersmayberesponsiblefortoxiceffectsas wellasresulting insuboptimalantibioticconcentrations below thoserequiredtobeeffectiveagainstMDRpathogens[2,4].

Subtherapeuticantibioticconcentrationsmayleadto antimi-crobialresistance,whichthreatensthemanagementofbacterial infectionsincriticallyillpatients.Moreover,escalating antimicro-bialresistancehassubstantiallyincreasedoverallhealthcarecosts asaresultofprolongedhospitalisationassociatedwithtreatment failures and the need for implementation of broader infection

Fig.1.Meandrugconcentration–timecurvescorrespondingtodosagesof(A)2gq8h,(B)1gq8hand(C)1gq12h.Barsindicatetheconﬁdenceintervalsforthemeanvalue. q8h,every8h;q12h,every12h.

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controlinterventionsaimedatreducingthespreadof antibiotic-resistantpathogens[1–5].

Therefore, PK studies are necessary to produce accurate recommendationsthat canbeusedas anadditionaltool inthe managementofinfections[8].

Sofar,fewdataareavailableregardingthepharmacokinetic/ pharmacodynamic(PK/PD)meropenemtargetforefﬁcacy, espe-cially in burn patients. Data from intensive care unit patients describedanareaundertheconcentration–timecurvefrom0–24h (AUC0–24), trough serum concentration (Cmin) and peak serum

concentration (Cmax) of 226mgh/L, 3.3mg/L and 28.4mg/L

respectively,asPK/PDtargets[3,6,9_–14].

Moreover, published data have described an AUC0–24/MIC

(minimuminhibitoryconcentration)ratioand%fT>MIC(percentage

oftimethatthedrugconcentrationremainsabovetheMIC)of125 and 75%, respectively, as the most signiﬁcant parameters to evaluatethetherapeuticefﬁcacyofmeropenem[3,6,9–14].

The aim of thisprospective studywas to describe the PK/PD parametersofmeropeneminburn patientstreatedwitha2-hinfusion.

2.Materialsandmethods

AllpatientsadmittedtotheBurnCenterofCTOHospital,Città dellaSaluteedellaScienza(Turin,Italy)fromJanuary2016toApril 2018 and treated with meropenem as empirical or targeted therapywereprospectivelyenrolledinthestudy.Meropenemwas administeredasa2-hintravenous(i.v.)infusionatadosageof1g every8h(q8h)upto2gq8haccordingtotheclinical character-isticsofthepatient.

ThestudywasapprovedbythelocalEthicalCommitteeofAOU CittàdellaSaluteedellaScienza,andwritteninformedconsent was obtained from patients before sampling. The study was performed in accordance with International Conference on Harmonisation Good Clinical Practice (ICH-GCP) guidelines and theDeclarationofHelsinki.

2.1.Patientcharacteristics

Informationregardingdemographicandclinicalcharacteristics wascollectedforeach patient,includingdaysofhospitalisation, lengthofstayintheunitandspeciﬁcburnindex.

SepsisandsepticshockwereclassiﬁedaccordingtotheThird InternationalConsensus Deﬁnitionsfor Sepsisand SepticShock (Sepsis-3)[15].Mortalitywasevaluatedatdischarge.

Microbiologicaldatawerealsocollectedwhenavailable.Incase oftargetedtherapy,foreachpatientthemicro-organism,siteof infectionandMICwerereported.

2.2.Bloodsamplingandmeropenemassay

Plasmameropenemconcentrationsweredeterminedat steady-state48hafterthebeginningoftherapy.TheCmincorrespondsto

concentrationbeforeadministrationandtheCmaxisdeﬁnedasthe

concentration at the end of the infusion. The AUC0–24 of

meropenem was calculated with blood sample collection by multiplyingtheAUCvaluescorrespondingtoeachdailydose(e.g.

AUC0–83)[10,13].

Bloodsampleswerecollectedbeforetheinfusion,attheendof the infusion (2h) and 5h after i.v. drug administration. Blood sampleswerecollectedinlithiumheparintubes(7mL)andplasma wasobtainedbycentrifugationat2800gfor10minat4C(ALC PK130Rrefrigeratedcentrifuge;DJBLabcareLtd.,NewportPagnell, UK).

Eachsamplewas storedat 20C untilanalysis(<3weeks). Stabilitytestsperformedduringmethodvalidationreporteddrug stability(<5%degradation)within1month(datanotshown).

T able 2 Simulate d pharmacokinetic/pharmacodynamic data for differ ent h ypo thetical minimum inhibit ory concentr ations (MICs). Pt. ID A U C0 – 24 /MIC T> MIC (% o v er 6, 8 o r 1 2 h ) a MIC =0.5 mg/L MIC = 1 m g/L MIC =2 mg/L MIC =0.5 mg/L MIC =1 mg/L MIC = 2 mg/L (EC OFF suscep tible) MIC = 8 m g/L (ECOFF resista nt) MIC =1 2 m g/L (6 EC OFF MIC) 1 365 1 8 3 9 1 1 0 0 1 0 0 1 0 0 43 25 2 1 54 77 39 4 7 42 3 7 2 7 0 3 3 70 1 8 5 9 3 1 0 0 1 0 0 1 0 0 58 40 4 362 1 8 1 9 1 1 0 0 1 0 0 1 0 0 68 49 5 469 234 11 7 1 0 0 92 78 5 1 43 6 4 7 3 23 7 11 8 1 0 0 1 0 0 93 56 45 7 487 244 1 2 2 1 0 0 93 79 52 4 4 8 3 0 0 15 0 7 5 1 0 0 10 0 8 0 4 2 3 1 9 455 22 7 11 4 48 4 4 4 1 33 3 1 1 0 405 203 1 0 1 1 0 0 1 0 0 1 0 0 65 48 11 7 3 0 3 6 5 1 8 3 1 00 1 0 0 1 00 1 0 0 7 7 1 2 950 4 7 5 2 3 7 1 0 0 1 0 0 1 0 0 9 1 7 3 1 3 906 453 22 7 5 2 4 8 4 5 3 7 3 5 1 4 2 1 6 1 08 54 1 0 0 8 5 7 0 4 0 3 1 1 5 1 5 7 3 786 393 1 0 0 1 0 0 1 0 0 1 0 0 1 0 0 1 6 920 460 230 1 0 0 1 0 0 1 0 0 9 1 7 5 1 7 389 1 9 5 9 7 1 0 0 1 0 0 1 0 0 56 42 Pt., patient ; A UC 0 – 24 , are a under the concentr ation – time curv e fr o m 0– 24 h; T> MIC , time that the drug concentr ation remains abo v e the MIC; EC OFF , epidemiological cut-off. a 1 0 0% indicates a cov er age 1 0 0% of the dosing int erv al.

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Meropenemquantiﬁcationwasperformedbyan ultra-perfor-mance liquid chromatography–photodiode array (UPLC-PDA) method,validated following US Food and Drug Administration (FDA)andEuropeanMedicinesAgency(EMA)guidelines.Brieﬂy, 200

m

L of plasma was added to 50

m

L of internal standard (thymidine)andunderwentproteinprecipitationwith400

m

Lof acetonitrile:methanol(50:50v:v)andthenwasdiluted1:10with purewaterbefore injectionona ACQUITYUPLCHSST3column (2.1150mm,1.8

m

m) (Waters Corp., Milford,MA,USA). Chro-matographicseparationwasachievedinagradientrunof10mM KH2PO4(pH3.2)andacetonitrilefor13minat40Cwithaﬂowof

0.4mL/min.

Accuracyaswellasintradayand interdayprecisionwereall within the limits imposed by the FDA and EMA guidelines (deviations from nominal concentration and coefﬁcients of variationboth<15%).Calibrationcurveswerelinearintherange of 0.585–15mg/L, with R2_>_0.996 _for _each _analytical _session.

Sampleswith plasma concentrations >15mg/L werediluted in order to ﬁt the linearity range, demonstrating good dilution integrityafterserialdilutions.

All PK parameters were calculated by means of a non-compartmental model using Kinetica software (Thermo Fisher Scientiﬁc,Waltham,MA,USA)andaresummarisedinTable1and representedgraphicallyinFig.1.

SimulateddataformeropenemPKparameterscalculatedwith MICs corresponding to 0.5, 1 and 2mg/L [susceptible by epidemiologicalcut-offvalue(ECOFF)],8mg/L(resistantbyECOFF) and12mg/L(6ECOFFMIC)werecalculatedbyconsideringa log-lineareliminationkineticinaccordancewiththeexperimentally determinedhalf-life(t1/2)(Table2).

Differencesbetweendifferentdrugdosages(1gvs.2gthree times a day) in terms of AUC or Cmin were through a

non-parametricMann–Whitneytest usingIBMSPSSStatistics v.24.0 (IBMCorp.,Armonk,NY,USA).Statisticalcomparisonsforpatients treatedwith1gevery12hor1gevery6hwerenotperformed considering the small sample size (two and one patients, respectively).

3.Results

Seventeenpatientswereenrolledinthestudy.Allpatientswere aged>25yearsandhadsevereinjuries[second-orthird-degree thermalinjuriesrangingfrom5–55%of theirtotal bodysurface area(TBSA)](Table1).

The majority of patients were male (13/17; 76%), with a meanstandard deviation (S.D.) age of 5718.3 years, a meanS.D. TBSAof3416.4%,a meanS.D.body massindex (BMI) of 25.24.7, a mean serum creatinine concentration of 0.85mg/dL andameancreatinineclearanceof134mL/min.The meantotalproteinserumconcentrationwas5.8g/dL(Table1).

Most patients were receiving mechanical ventilation (9/17; 53%)andhadanindwellingcentralarterialline(14/17;82%)atthe timeofinfection(Table1).

Thirteen patients (76%) were treated with meropenem as targetedtherapyforinfectionscausedbyMDRP.aeruginosaorA. baumanniiisolatedfrombloodorwounds.Accordingtothe Sepsis-3criteria[15],12patients(71%)hadsepsisand3(18%)hadseptic shock.Therewerenodeathsat14daysfromhospitaladmission, whilstmortalityatdischargewas12%(2/17)withameanrevised Bauxscore[16,17]of103.ThemainmeropenemPKparametersare reportedinTable1andtheAUCvaluesarepresentedinFig.1.The mean Cmax, Cmin, AUC0–24, t1/2, drug clearance and volume of

distribution (Vd) were 28.9mg/L, 3.7mg/L, 280.2mgh/L, 2.0h,

19.0L/hand44.4L,respectively.

Sixpatients(35%)achievedaCmin3.3mg/Landsevenpatients

(41%) achieved a Cmax>28.4mg/L, whilst nine patients (53%)

achievedan AUC0–24of >226mgh/L.No statisticallysigniﬁcant

differences in PK parameters wereobserved between different dosingregimens(P-values of0.787for AUC,0.324forCmaxand

0.510forCmin).

SimulateddataformeropenemPKparameterscalculatedwith MICscorrespondingto0.5,1,2(ECOFF),8and12mg/L(6ECODD MIC)arereportedinTable2.

GivenanMICof0.5mg/L,allpatientssatisﬁedthetargetAUC/ MICof>125,butwhentheMICroseto2mg/L(ECOFF),onlyﬁve patientsreachedthedesiredAUC/MIC.RegardingfT>MICatanMIC

of2mg/Lwithaprolongedinfusiontimeof2h,13patients(76%) achievedthepharmacokinetictarget(_>75%).

4.Discussion

Severe infections are the main cause of death among burn victims, mainly due toloss of the natural skin barrier against pathogenicmicro-organisms. Moreover,coagulatedproteinsand othermicrobialnutrientsinthelesionaswellaslocal avascular-isationleadtobacterialcolonisationand facilitateaccesstothe systemiccirculation[3].

Antibiotic therapies are usually difﬁcult to manage in this setting,sincepatientswithmajorburnsexperiencepathological changesthathavebeenshowntoinﬂuencethepharmacokinetics of antibiotics. Subsequently, it has been demonstrated that conventional doses of some antibiotics given to patients with majorburnsmayresultinsubtherapeuticserum concentrations withunsuccessfulmicrobiologicalandclinicalcure[1–4].

Moreover,theincreasingincidenceofinfectionscausedbyMDR Gram-negativeinfectionsinthissettingposesagreatchallengefor cliniciansaimingtoprovidemaximallyeffectivetherapy.

HerewereportthemainPK/PD ﬁndingsofa2-hinfusionof meropenem in burn patients aimed at identifying the best treatment option in this setting. The patients included in this studyhadameanrevisedBauxscoreof103,indicatingthatinthis grouptheexpectedmortalityrangesfrom30–55%dependingon age,burnextensionandconcomitantinhalationinjury;noticeably, observedmortalityathospitaldischargewas12%.

The results showed wide PK variability among patients, as alreadyhighlightedinpreviousstudiesonsimilarpopulationsof critical patients owing to the peculiar pathophysiological con-ditions[6,18].Deepeningthisissue,intermsofdosageortiming, dosingregimenswereadjustedonthebasisofpatient character-istics(i.e.renalinsufficiency,dialysis,renalreplacementtherapy, fluidoverload,degreeofburns),leadingtosatisfactoryPKcoverage throughout 24h. This wasfurtherconfirmed bytheabsenceof significant differencesin termsof drugconcentrationsbetween differentdosingregimens(Fig.1).

ThemeanCminandCmaxvalueswerefoundtobesimilartothose

reportedintheliteraturein65%and59%ofpatients,respectively

[3,6,9_–14]. Of note, for TBSA50%, only two patients had a

Cmin3.3mg/L and only one patient had a Cmax>28.4mg/L,

suggestingthatthepercentageTBSAmightstronglyaffecttheVd

andotherphysiologicalparameters,althoughinthecurrentstudy nostatisticallysigniﬁcantcorrelationwasfound,possiblydueto thesmallnumberofpatientsenrolled.

Despitethe2-hi.v.infusion,patientsinthisstudyhadlower AUC0–24compared withdata fromtheliterature,and onlynine

patients (53%) achieved the target of >226mgh/L [3,6,9–14]. Moreover,anAUC/MICof125wasachievedinallpatientsexcept onewhentheMICwas0.5mg/Lor1mg/L,whereastheproportion ofpatientsreachingthisPK/PDtargetdecreasedprogressivelyat higherMICs.

Considering the targeted fT>MIC (75%), the vast majority of

patients(76%)achievedasatisfactoryfT>MICwhenanMICof2mg/L

wasconsidered.

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This proposal is also supported by a recently published populationPKanalysisinsepticshockpatientswhereprolonged or continuous infusion and increased dosages of meropenem appeared to enhance therapeutic effectiveness, particularly in patients with augmented renal clearance [14]. Moreover, pro-longedinfusionofmeropenemappears tobeassociatedwitha higherclinicalimprovementrateandalowermortalityinsevere infection [19]. According to data from a different setting of criticallyillpatients,thecurrentdatasupporttheideathatburn patientsmayalsobeneﬁtfromprolongedinfusionofahighdosage ofmeropenem(2gq8h),possiblywithaloadingdose,regardlessof augmentedrenalclearance[14,19,20].

Moreover, according to the need for better personalised therapy,amoreactiveapproachwithroutineuseoftherapeutic drugmonitoringappearstobeeffectivetoreducetoxicityandto improveefﬁcacy,especiallyinburnpatients.

Funding None.

Competinginterests

Nonedeclared. Ethicalapproval

ThisstudywasapprovedbythelocalEthicalCommitteeofAOU CittàdellaSaluteedellaScienza(Turin,Italy)[PROT.No.0063741]. Written informed consent was obtained from patients before sampling.Thestudywasperformedinaccordancewith Interna-tionalConferenceonHarmonisationGoodClinicalPractice (ICH-GCP)guidelinesandtheDeclarationofHelsinki.

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