Assessing the Efficacy and Safety of Eravacycline vs Ertapenem in Complicated Intra-abdominal ...

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Research
JAMASurgery | OriginalInvestigation
Assessing the Efficacy and Safety of Eravacycline
vs Ertapenem in Complicated Intra-abdominal Infections
in the Investigating Gram-Negative Infections Treated
With Eravacycline (IGNITE 1) Trial
A Randomized Clinical Trial
JosephSolomkin,MD;DavidEvans,MD;AlgirdasSlepavicius,MD;PatrickLee,MD;AndrewMarsh;LarryTsai,MD;
JoyceA.Sutcliffe,PhD;PatrickHorn,MD
Supplementalcontent
IMPORTANCEEravacyclineisanovel,fullysyntheticfluorocyclineantibioticofthetetracycline
CMEQuizat
classwithinvitroactivityagainstclinicallyimportantgram-negative,gram-positiveaerobic, jamanetworkcme.com
andfacultativebacteriaincludingmostofthoseresistanttocephalosporins,
fluoroquinolones,β-lactam/β-lactamaseinhibitors,multidrugresistantstrainsand
carbapenem-resistantEnterobacteriaceae,andmostanaerobicpathogens.
OBJECTIVE Toevaluatetheefficacyandsafetyoferavacyclinecomparedwithertapenemin
adulthospitalizedpatientswithcomplicatedintra-abdominalinfections(cIAIs).
DESIGN,SETTING,ANDPARTICIPANTS ThiswasaphaseIII,randomized,double-blind,
multicenterstudythatevaluatedtheefficacyandsafetyoferavacyclineincomparisonwith
ertapeneminpatientswithcIAIrequiringsurgicalorpercutaneousintervention.The
test-of-cureevaluationwasconducted25to31daysafterthefirstdoseofthestudydrugand
thefollow-upvisitwasconducted38to50daysafterthefirstdoseofthestudydrug.All
patientsrecruitedintothisstudywerehospitalized.Fivehundredforty-onepatientswere
recruitedforthisstudy;270patientswererandomizedtoreceiveeravacycline,and271
patientswererandomizedtoreceiveertapenem.Patientshadtomeetallofthefollowing
criteria:hospitalizedforcIAIrequiringintervention;18yearsorolder;evidenceofsystemic
inflammatoryresponse;paincausedbycIAI;abletoprovideinformedconsent;anddiagnosis
ofcIAIwithsonogramorradiographicimagingorvisualconfirmation.Analysesweredonein
intent-to-treatandevaluablepopulations.
INTERVENTIONS Patientsreceivederavacycline,1.0mg/kgevery12hours,orertapenem,1.0
gevery24hours,foraminimumoffour24-hourdosingcycles.
MAINOUTCOMESANDMEASURES Clinicaloutcomeassessmentsweremadeattheendof
treatment,testofcure,andfollow-upvisitsandwereclassifiedasclinicalcure,clinicalfailure,
orindeterminate/missing.
RESULTS Intotal,541patientswererandomlyassignedtotreatment:270intheeravacycline
groupand271intheertapenemgroup.Themeanageswere54.9yearsand55.4yearsforthe AuthorAffiliations:Universityof
eravacyclineandertapenemgroups,respectively.Mostpatientswerewhite(263of270 CincinnatiCollegeofMedicine,
patients[97.4%]intheeravacyclinegroupand260of271patients[95.9%]intheertapenem Cincinnati,Ohio(Solomkin);Ohio
StateUniversitySchoolofMedicine,
group).Forthemicrobiologicalintent-to-treatpopulation,theratesofclinicalcureatthe
Columbus(Evans);Klaipeda
test-of-curevisitwere86.8%intheeravacyclinegroupand87.6%intheertapenemgroup. UniversityHospital,Klaipeda,
Thedifferenceinclinicalcureratesbetweenthegroupswas−0.80%(95%CI,−7.1%to5.5%), Lithuania(Slepavicius);Baystate
MedicalCenter,Springfield,
meetingtheprespecifiednoninferioritymarginandallowingforstatisticalnoninferiorityof
Massachusetts(Lee);Tetraphase
eravacyclinetoertapenemtobedeclaredforthisstudy.Bothstudydrugswerewelltolerated.
PharmaceuticalsInc,Watertown,
Massachusetts(Marsh,Tsai,Sutcliffe,
CONCLUSIONSANDRELEVANCE Overall,eravacyclinedemonstratednoninferiorityto Horn).
ertapenemforthetreatmentofpatientswithcIAI. CorrespondingAuthor:JosephS.
Solomkin,MD,Departmentof
TRIALREGISTRATION Clinicaltrials.gNCT01844856. Surgery,UniversityofCincinnati
CollegeofMedicine,6005GivenRd,
JAMASurg.2017;152(3):224-232.doi:10.1001/jamasurg.2016.4237 Cincinnati,OH45243
PublishedonlineNovember16,2016. ([email protected]).
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EravacyclinevsErtapeneminComplicatedIntra-abdominalInfections OriginalInvestigation Research
G
ram-positiveandgram-negativeorganismswithnovel
resistancemechanismstocommonlyusedantimicro- KeyPoints
bialshavebecomeaglobaltherapeuticproblem.The
Question Iseravacyclineasafeandeffectivetreatmentfor
estimatesofmortalityandcostsowingtoantimicrobialresis- complicatedintra-abdominalinfectionscomparedwith
tancearestriking,andtheseconcernshaveledtoclinicaland ertapenem?
governmentalaction.1-3
Findings Thisrandomizedclinicaltrialof541patientswith
Acommonresistancemechanismistheproductionof
complicatedintra-abdominalinfectionsrequiringsurgeryor
extended-spectrumβ-lactamases(ESBLs).4Organismsthat percutaneousdrainagefoundacurerateof86.8%forthe
produceESBLsarenowmostcommonlyrecognizedinhealth microbiologicalintent-to-treatpopulationintheeravacycline
caresettingsandare,ifnotappropriatelytreated,anindepen- treatmentgroupand87.6%forthemicrobiologicalintent-to-treat
dentriskfactorforincreasedmorbidityandmortality.5,6Other populationintheertapenemtreatmentgroup.Thedifferencein
clinicalcurerateswas−0.80%,exceedingtheestablished
importantpathogens,suchasthoseintheAcinetobacterbau-
noninferioritymargin.
maniicomplex,areroutinelymultidrugresistant.7,8
Eravacyclineisanovel,fullysyntheticantibioticofthe Meaning Theefficacy,microbiologicalactivity,andsafetyof
tetracyclineclassdesignedtobeactiveagainstthe2mainac- eravacyclinesupportapositiverisk-benefitprofileforthe
treatmentofpatientswithcomplicatedintra-abdominalinfections
quiredtetracycline-specificresistancemechanisms:ribo-
andarecomparablewiththeknownprofileforertapenem.
somalprotectionandactivedrugefflux.9,10Eravacyclinehas
potentinvitroactivityagainstantibiotic-resistantbacteria
identifiedasurgentorseriousthreatsbytheUSCentersfor
DiseaseControlandPrevention:carbapenem-resistantEn- PatientswereenrolledbetweenthedatesofAugust28,
terobacteriaceae,methicillin-resistantStaphylococcusau- 2013,andAugust24,2014,from66clinicalsitesin11coun-
reus,ESBL-producingEnterobacteriaceae,andvancomycin- tries(FlorenceandMobile,Alabama;Glendale,LaMesa,
resistantenterococci.11 LosAngeles,andTorrance,California;Aurora,Illinois;Car-
Adose-findingphaseIIstudysupportedtheefficacyof mel,Indiana;BostonandSpringfield,Massachusetts;Min-
eravacyclineincomplicatedintra-abdominalinfections neapolis,Minnesota;LasVegas,Nevada;CamdenandTea-
(cIAIs),12animportantprobleminclinicalpractice.13Treat- neck,NewJersey;Cleveland,Columbus,andWeston,Ohio;
mentfailure,describedassurgicalsiteinfections,maycause Houston, Texas; and Seattle, Washington in the United
substantialmorbidity,mortality,delayedrecovery,andin- States;Corboda,Argentina;Pleven,Plovdiv,Rousse,Sofia,
creasedcosts.14-16Forthesereasons,cIAIsremainanim- and Varna, Bulgaria; Brno, Kladno, Melnik, Olomouc,
portantdiseaseprocessforexaminingtheefficacyofnovel Prague,andUstinadLabemintheCzechRepublic;Kohtla-
antibiotics. Jarve,Tallinn,TartuinEstonia;Paris,France;Heidelberg,
Becauseresistant,gram-negativeorganismsareadocu- Luebeck,andMagdeburg,Germany;Daugavpils,Liepaja,
mentedproblemincIAIs,thereisaclearneedforbroad- andRiga,Latvia;Kaunas,Klaipeda,Siauliai,andVilnius,
spectrumantibioticstocoverthewiderangeofpotentialpatho- Lituania;Bucharest,Cluj-Napoca,Craiova,andTimisoara,
gensseen.Theobjectiveofthisstudywastoassesstheefficacy Romania;Kaluga,Kemerovo,Moscow,NizhnyNovgorod,
andsafetyoferavacyclinecomparedwithertapeneminthe Smolensk,StPetersburg,Tomsk,Volgograd,andVsevolo-
treatmentofcIAIsinhospitalizedadults. zhskoftheRussianFederation;Benoni,Johannesburg,Pre-
toria,andWorcester,SouthAfrica;andDnipropetrovsk,
Ivano-Frankivsk, Kharkiv, Kyiv, Odesa, Uzhhorod, and
ZaporizhiaintheUkraine).Theformaltrialprotocolsforthe
Methods
studycanbefoundintheSupplement.
StudyDesign
This was a randomized, double-blind, double-dummy, InclusionCriteria
multicenterstudyusinga2-arm,paralleltreatmentgroup Patientswere18yearsorolderwithclinicalevidenceofcIAI
designthatcompliedwiththemostrecentUSFoodandDrug requiring urgent surgical or percutaneous intervention
Administration(FDA)guidance.17Thestudywasdesignedto within48hoursofdiagnosis.Requirementsforpreoperative
demonstratenoninferiorityoferavacycline(1.0mg/kgper12 enrollmentweresonogramorradiographicimagingresults
hours)vsertapenem(1.0gper24hours). consistentwiththediagnosisofcIAI;plannedacutesurgical
Theprotocolandallsupportinginformationweresubmit- orpercutaneousintervention;andplannedspecimencol-
tedtoandapprovedbytheinstitutionalreviewboardorin- lectionbyaspirationortissuesamplesentforcultureand
dependentethicscommitteeateachsitebeforethestudywas sensitivity.AcceptablediagnosesforcIAIwereappendiceal
initiated.ThestudywasconductedinaccordancewithGood perforationand/orperiappendicealabscess;diverticulitis
ClinicalPracticeandtheWorldMedicalAssemblyDeclara- abscessorperitonitis;acutegastricandduodenalperfora-
tionofHelsinki.Eachpatientofageofconsent(perlocalre- tionifoperatedonmorethan24hoursaftertheperforation;
quirements)signedanddatedastudy-specificinformed traumaticperforationoftheintestinesifoperatedonmore
consentformbeforeanystudyprocedureswereconducted. than12hoursaftertheperforation;and/orabscessorperito-
Theconsentformscompliedwithallapplicableregulations nitisowingtoperforatedviscusorotherfocusofinfection
governingtheprotectionofhumanparticipants. orotherintra-abdominalabscess.
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Research OriginalInvestigation EravacyclinevsErtapeneminComplicatedIntra-abdominalInfections
Figure.CONSORTDiagram
583Patients assessed for eligibility
42Excluded
32Did not meet inclusion criteria
10Declined to participate
541Randomized
270Randomized to receive eravacycline 271Randomized to receive ertapenem
268Received intervention as
randomized
3Did not receive intervention
as randomized
2Withdrew consent
1Randomized in error
19Lost to follow-up 21Lost to follow-up
12Discontinued intervention 9Discontinued intervention
1Did not meet disease criteria 1Did not meet disease criteria
3Receipt of confounding non- 5Did not have adequate source
study antibiotic control
5Did not have adequate source 3Did not receive at least 3 d
control of study drug
2Did not receive at least 3 d
of study drug
1Met key exclusion criteria
229Included in the primary analysis 236Included in the primary analysis
10Excluded from analysis 2Excluded from analysis
5Adverse event (adverse event)
3Insufficient therapeutic effect
2Other
ExclusionCriteria ofinfection(complicatedappendicitisvsallotherdiagno-
Thefollowingexclusionsapplied:rapidlyprogressingdis- ses).Nomorethan30%ofpatientsenrolledweretohavecom-
easeorimmediatelylife-threateningillnessincludingacutehe- plicatedappendicitis.Eligiblepatientswereassignedtore-
paticfailure,respiratoryfailure,and/orsepticshock;require- ceiveanintravenousinfusionoferavacycline,1.0mg/kgevery
mentofvasopressorsattherapeuticdosagestomaintaina 12hours,orertapenem,1gevery24hours.Thestudydrugwas
systolicbloodpressureatleast90mmHgordiastolicblood administeredin24-hourdosingcyclesforaminimumof4dos-
pressureatleast70mmHg;acreatinineclearancelessthan ingcycles.Drugassignmentwasconcealedfromthepatient
50mL/minasestimatedbytheCockcroft-Gaultequation(to andallclinicalandstudystaffusingplaceboinfusionsanda
converttomilliliterspersecondspermeterssquared,multi- double-dummydesign.Thecomparator,ertapenem,isap-
plyby0.0167);and/orpossiblesignsofsignificanthepatic provedbytheFDAandotherregulatoryauthoritiesforthe
diseasedefinedasalanineaminotransferaseoraspartateami- treatmentofcIAI.
notransferasegreaterthan3timestheupperlimitsofnor-
mal;greaterthan5timestheupperlimitsofnormalforpa- OutcomeAssessment
tientswithhepaticabscessortotalbilirubingreaterthan3times Patientswereevaluatedonday1throughday14ofthedrug
theupperlimitsofnormal;anticipatedsurvivalperiodshorter regimenandattheend-of-treatmentvisit,whichoccurred
thanthestudyperiod;symptomsrelatedtodiagnosisofcom- within24hoursofthelastdoseofthestudydrug.Thetest-
plicatedappendicitisforlessthan24hourspriortothecur- of-cure(TOC)evaluationwasconducted25to31calendar
renthospitalization;plannedtreatmentofcIAIbystagedab- daysafterthefirstdoseofthestudydrugwasadministered,
dominalrepairorotheropenabdominaltechniques;and/or andthefollow-upvisitwasperformed38to50calendar
knownorsuspectedinflammatoryboweldiseaseorassoci- daysafterthefirstdoseofstudydrugwasadministered.
atedvisceralabscess.Patientswereexcludediftheyhadre- Patientsremainedhospitalizedfortheentirecourseofdrug
ceivedsystemicantibioticsfortheirconditionformorethan therapy.
24hours,receivedertapenemoranyothercarbapenemorti- Clinicalresponseswereclassifiedasclinicalcure,clinical
gecyclinefortheinfection,orrequiredsystemicantimicro- failure,orindeterminate/missing.Clinicalcurewasdefined
bialagentsotherthanthestudydrug. ascompleteresolutionorsignificantimprovementofsignsor
symptomsoftheindexinfectionsuchthatnoadditional
RandomizationandTreatment antibacterialtherapy,surgical,orradiologicalintervention
Randomizationnumberswerecomputergeneratedusingan wasrequired.Eventsdefiningclinicalfailureincludeddeath
internet-basedsystemandstratifiedbasedontheprimarysite relatedtocIAIatanytime,persistenceofclinicalsignsand
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EravacyclinevsErtapeneminComplicatedIntra-abdominalInfections OriginalInvestigation Research
Table1.Demographics,Baseline,andSurgicalCharacteristics(Micro-ITTPopulation)
No.(%)
Eravacycline,1.0mg/kg Ertapenem,1.0g
Every12h Every24h
Characteristic (n=220) CureRate (n=226) CureRate
Malesex 126(57.3) NA 132(58.4) NA
BMI,mean(SD)[range] 28.23(5.77) NA 27.50(5.04) NA
[17.3-73.6] [17.3-46.4]
Age,mean(SD)[range],y 54.9(17.14) NA 55.4(16.17) NA
[19-86] [20-87]
Agegroup,y
<65 149(67.7) 132(88.6) 159(70.4) 142(89.3)
65-74 43(19.5) 33(76.7) 36(15.9) 28(77.8)
≥75 28(12.7) 26(92.9) 31(13.7) 28(90.3)
APACHEIIscore,mean(SD) 6.6(4.23) NA 6.8(3.94) NA
[range] [0-30] [0-22]
Surgicalintervention
Open 126(57.3) 108(85.7) 135(59.7) 117(86.7)
Laparoscopic 69(31.4) 60(87.0) 71(31.4) 64(90.1)
Percutaneous 25(11.4) 23(92.0) 20(8.8) 17(85.0)
Primarydiseasediagnosisas
randomized
Complicatedappendicitis 65(29.5) NA 67(29.6) NA
OthercIAI 155(70.5) NA 159(70.4) NA
Finaldiagnosisand
intraoperativefindings
Totalappendicitis 68(30.9) 58(85.3) 67(29.6) 58(86.6)
Perforatedappendicitis 26(36.8) 22(84.0) 27(40.2) 22(81.5)
Abscess 15(19.1) 11(76.9) 18(20.9) 17(100.0)
Peritonitis 27(39.7) 25(92.6) 22(53.7) 19(86.4)
Totalcholecystitis 44(20.0) 39(88.6) 47(20.8) 46(97.9)
Complicatedcholecystitis 19(43.2) 18(94.7) 17(36.2) 17(100.0)
Abscess 17(38.6) 15(88.2) 19(40.4) 19(100.0)
Peritonitis 5(11.4) 4(80.0) 7(14.9) 6(85.7)
Abscessandperitonitis 3(6.8) 2(66.7) 4(8.5) 4(100.0)
Gastrointestinal/duodenal 20(9.1) 19(95.0) 26(11.5) 25(96.2)
perforation(peritonitis)
Hepatic 19(8.6) 19(100.0) 6(2.7) 5(83.3)
Totalintestinalperforation 31(14.1)1 24(77.4) 41(18.1)2 34(82.9)
Abscess 9(29.0) 7(77.8) 9(22.0) 7(77.8)
Peritonitis 20(64.5) 15(75.0) 22(53.7) 20(90.9)
Abscessandperitonitis 2(6.5) 2(100.0) 10(24.4) 7(70.0)
Gynecological 3(1.4) 3(100.0) 1(0.4) 1(100.0)
Organsourcenotspecified 21(9.5) 18(85.7) 24(10.6) 17(70.8)
Abscess 17(81.0) 14(82.4) 20(83.3) 14(70.0)
Peritonitis 3(14.3) 3(100.0) 4(16.7) 3(75.0)
Abscessandperitonitis 1(4.8) 1(100.0) 0(0.0) 0
Totalpostsurgical 13(5.9) 10(76.9) 14(6.2) 12(85.7) Abbreviations:APACHE,Acute
PhysiologyandChronicHealth
Splenicabscess 1(0.5) 1(100.0) 0(0.0) 0
Evaluation;BMI,bodymassindex
Durationoftreatment,d (calculatedasweightinkilograms
dividedbyheightinmeterssquared);
Median 7.0 NA 7.0 NA
cIAI,complicatedintra-abdominal
Mean(SD)[range] 7.6(2.8) NA 7.6(2.4) NA infections;ITT,intent-to-treat;
[2-15] [2-15]
NA,notapplicable.
symptomsofcIAI,unplannedsurgicalproceduresorpercu- teriaforclinicalcureorclinicalfailurewerelistedasindeter-
taneousdrainageprocedures,postsurgicalwoundinfections minate.Iftheinvestigatordidnotcompleteanassessmentor
requiringsystemicantibiotics,andinitiationofadditionalan- ifthepatientwasnotpresentfortheTOCstudyvisit,theout-
tibacterialdrugtherapyforcIAI.Patientswhodidnotmeetcri- comewasconsideredmissing.
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Research OriginalInvestigation EravacyclinevsErtapeneminComplicatedIntra-abdominalInfections
Table2.PrimaryEfficacyAnalysisforUSFoodandDrugAdministration(ClinicalResponseatTOCVisit)
No.(%)
Eravacycline,1.0mg/kg Ertapenem,1.0g
Population Every12h Every24h Difference(95%CI)
MITT
No. 270 268
Clinicalcure 235(87.0) 238(88.8)
−1.80(−7.4to3.8)
Clinicalfailure 19(7.0) 15(5.6)
Indeterminate/missing 16(5.9) 15(5.6)
Micro-ITT
No. 220 226
Clinicalcure 191(86.8) 198(87.6)
−0.80(−7.1to5.5)
Clinicalfailure 19(8.6) 11(4.9)
Indeterminate/missing 10(4.5) 17(7.5)
CE
No. 239 238
Clinicalcure 222(92.9) 225(94.5) −1.7(−6.3to2.8)
Clinicalfailure 17(7.1) 13(5.5)
Microbiologicallyevaluable
No. 198 199 Abbreviations:CE,clinically
Clinicalcure 181(91.4) 189(95.0) −3.6(−8.9to1.5) evaluable;ITT,intent-to-treat;
MITT,modifiedintent-to-treat;
Clinicalfailure 17(8.6) 10(5.0)
TOC,test-of-cure.
MicrobiologicAssessment theertapenem1.0gevery24hoursgroup.TheCONSORTdia-
Fourbloodsamplesfromatleast2separatevenipuncturesites gramindicatingdifferentpatientpopulationsisshowninthe
wereobtainedatthetimeofscreeningforaerobeandanaerobe Figure.Patientswhohadbaselinebacterialpathogensagainst
cultures.Surgicalspecimensfromallsiteswereshippedto atleast1ofwhichthestudydrughadinvitroantibacterialac-
theirrespectiveregionallaboratoryatambienttemperature tivityweredesignatedasthemicro-ITTpopulation.Thede-
onthedayofcollectionwitharrivalwithin48hoursfromthe mographicsandbaselinecharacteristicsforthispopulationare
timeofcollectionforpurificationandidentificationofiso- showninTable1.
lates.Allbacterialisolatesculturedfromaerobicandanaero- Patientsinthemicro-ITTpopulationdisplayedgener-
bicspecimenswereevaluatedforsusceptibilitytostudy allysimilardemographiccharacteristicsacrossbothtreat-
drugs.Isolatesfromallstudiesshowingresistancetocarbap- mentgroups.Themeanageswere54.9yearsand55.4years
enemsorthird-andfourth-generationcephalosporinswere fortheeravacyclineandertapenemgroups,respectively.
senttoJMILaboratories,NorthLiberty,Iowa,todetermine Mostpatientswerewhite(263of270patients[97.4%]inthe
uniquenessbasedonpulsedfieldgelelectrophoresisandfur- eravacyclinegroupand260of271patients[95.9%]inthe
therdeterminationofβ-lactamresistancemechanisms. ertapenemgroup)andmen,reflectingthegeographicdistri-
butionofstudysites.
StatisticalAnalysis Approximatelyone-thirdofpatientsinbothtreatment
Theprimaryefficacyendpointwastheclinicalresponseatthe groups(88of270patients[32.6%]foreravacyclineand76of
TOCvisitinthemicrobiologicalintent-to-treat(micro-ITT)popu- 271patients[28.0%]forertapenem)wereolderthan65years.
lation(FDA)andinthemodifiedintent-to-treat(MITT)andclini- Webelievetheparadoxicallyhighcureratesinpatients75years
callyevaluablepopulations(EuropeanMedicinesAgency).For andolderwereowingtodiseaseswheretheinfectiouspro-
theFDA,anoninferioritymarginof10%wasused.Thenonin- cesscouldbeextirpatedsuchaspericholecysticdisease.
ferioritytestwasbasedonthelowerlimitofthe2-sided95%CI.
Ifthelowerlimitofthe95%CIforthedifferenceinclinicalcure PathologicProcessesEncountered
ratesinthemicro-ITTpopulationexceeded−10%,noninferior- Onehundredpatients(90.0%)intheeravacyclinetreatment
ityoferavacyclinetoertapenemwouldbedeclared. groupand189patients(83.6%)intheertapenemtreatmentgroup
Weperformedareviewofsourcecontrolproceduresfor enteredthestudyeitherintraoperativelyorpostoperatively.
patientswhoseclinicaloutcomeswereconsideredfailures Themostcommonanatomicdescriptionofinfectionwas
andcuredpatientswithanunplannedsecondprocedure.17 intra-abdominal abscess(es), with 85 patients (42.9) in the
eravacyclinetreatmentgroupand77(40.7%)intheertapenem
treatmentgroup,followedbyperitonitis(62patients[31.1%]and
65patients[34.4%]intheeravacyclineandertapenemgroups,
Results
respectively).Complicatedappendicitiswasthecauseofinfec-
PatientDemographicsandBaselineCharacteristics tionin62patients(31.3%)and60patients(31.7)intheerava-
Intotal,541patientswererandomlyassignedtotreatment:270 cyclineandertapenemgroups,respectively.Thedatadisplayed
intheeravacycline1.0mg/kgevery12hoursgroupand271in bythepresumedpathologyareprovidedinTable1.
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EravacyclinevsErtapeneminComplicatedIntra-abdominalInfections OriginalInvestigation Research
Mostpatientsinthemicro-ITTpopulationintheeravacy-
Table3.ReasonsforClinicalFailureatTOCVisit(Micro-ITTPopulation)
clinegroupandtheertapenemgrouphadopensurgicalpro-
cedures.Thesecondmostcommonoperativeapproachwas No.(%)
laparoscopic,followedbypercutaneousdrainage.Thechoices Eravacycline, Ertapenem,
1.0mg/kg 1.0g
weredrivenbythepathologyencountered;cholecystitiswas Every12h Every24h
mostoftentreatedbylaparoscopy,aswasappendicitis.Vari- Reason (n=220) (n=226)
ClinicalfailureatTOC 19(8.6) 11(4.9)
ablesrelatingtothesurgicalintervention,suchasaveragestudy
Unplannedsurgicalprocedureor 10(4.5) 9(4.0)
dayofintervention,numberofabscesses,infectiontype,
percutaneousdrainageprocedure
woundclosure,andnumberofdrainsplaced,weresimilarin
Initiationofrescueantibacterialtherapy 6(2.7) 4(1.8)
bothtreatmentgroups. forcIAI
PersistenceofclinicalsymptomsofcIAI 5(2.3) 4(1.8)
EfficacyAnalysis Postsurgicalwoundinfectionsrequiring 5(2.3) 2(0.9)
systemicantibiotics
Table2detailsthedifferenceinclinicalcureratesattheTOC
Other 3(1.4) 2(0.9)
visitbasedona95%CI.Fortheprimaryendpoint,clinicalcure
Surgicaladjudicationcommittee 0 1(1.4)
rateswere87.0%(235of270)foreravacyclineand88.8%(238
of268)forertapenemintheMITTpopulation.Thedifference Abbreviations:cIAI,complicatedintra-abdominalinfections;ITT,intent-to-treat;
TOC,test-of-cure.
inclinicalcurerateswas−1.80%witha2-sided95%CIof−7.4%
to3.8%,meetingthestatisticalcriteriafornoninferiority.The
microbiologicallyevaluablepopulationalsoachievedstatis- ovatus,Enterococcusfaecalis,andPseudomonasaeruginosa.
ticalnoninferiority,withclinicalcureratesof91.4%(181of198) Alsoofinterestisthefactthatthefavorableresponseinpa-
foreravacyclineand95.0%(189of199)forertapenem(differ- tientswithbaselineAcinetobacterbaumanniiwas100%inboth
enceof−3.6%;95%CI,−8.9%to1.5%).Clinicalcureratesin treatmentgroups(8of8foreravacyclineand5of5forertap-
theclinicallyevaluablepopulationatTOCwere92.9%(222of enem)attheTOCvisit.
239)and94.5%(225of238)withadifferenceof−1.7%(−6.3%
to2.8%).Inthemicro-ITTpopulation,curerateswere86.8% OrganismsPresentinTreatmentFailures
(191of220)and87.6%(198of226),respectively(difference Fifteenpatientsintheeravacyclinearmand11intheerta-
−0.80%;95%CI,−7.1%to5.5%). penemarmhadfailedclinicaloutcomesbecauseofneedfora
Clinicalfailureratesweresimilarinbothtreatmentgroups secondunplannedprocedureorwoundinfection.Tenpa-
fortheMITTpopulation.Forthemicro-ITTpopulation,the tientsreceivingeravacyclinehadpersistingisolates.These
clinicalfailureratewas8.6%(19of220)fortheeravacycline included6Escherichiacoliand1eachBacteroidesspecies,
treatmentgroupand4.9%(11of226)fortheertapenemtreat- Clostridiaperfringens,Enterococcusdurans,Hemophiluspara-
mentgroup,withindeterminate/missingratesof4.5%(10of influenzae,andPseudomonasaeruginosa.Intheertapenem-
220)and7.5%(17of226),respectively.Table3detailsallclini- treatedpatients,therewas1Ecoli,2Bacteroidesspecies,and
calfailuresinthemicro-ITTpopulation.Themostfrequentrea- 2streptococci.
sonsforclinicalfailurewereunplannedsurgicalprocedureor Inpatientswhoseoutcomeswereclassifiedasclinicalfail-
percutaneousdrainageprocedureandinitiationofrescue uresandwhounderwentasecondsurgicalprocedurethatal-
antibacterialtherapyforcIAI. lowedforrepeatedculture,thesusceptibilitytoeravacycline
Therewere9deathsinthestudy,3amongpatientsreceiv- ofthepathogensisolatedatthefollow-upprocedurewascom-
ingeravacyclineand6amongpatientsreceivingertapenem. paredwiththesusceptibilityoftheoriginalbaselinepatho-
Thespecificcausesofdeathwerepulmonaryembolism(n=2), gens.Only1patientintheeravacyclinegroupexhibitedde-
respiratoryfailure(n=3),multisystemorganfailure(n=1),car- creasingsusceptibility.
diacrhythmdisturbances(n=2),andcerebrovascularacci-
dent(n=1).Nonewereconsideredrelatedtostudytherapy. Safety
Thereweremoretreatment-emergentadverseeventsinthe
MicrobiologicResponses eravacyclinetreatmentgroup(113of270)thantheerta-
Table4summarizesthenumberandpercentageofpatients penemtreatmentgroup(75of268).Thenumberofsevereor
fromthemicro-ITTpopulationwithafavorablemicrobiologi- life-threateningtreatment-emergentadverseeventswasthe
calresponseattheTOCvisit.Thepercentageoffavorablere- sameforbothgroups(n=13).Thenumberofpatientswhoex-
sponseswasgenerallysimilarbetweentreatmentgroupsfor periencedtreatment-emergentadverseeventsbypreferred
mostpathogens.Thebaselinepathogensforwhichtheinci- termineachtreatmentgroupwassimilarforvomiting,ane-
denceoffavorableresponseswasatleast10%higherintheer- mia,pyrexia,anddiarrhea.Nauseaandphlebitiswerethe
avacyclinetreatmentgroupcomparedwiththeertapenem exceptions:nauseawasrecordedfor22patients(8.1%)inthe
treatmentgroupincludedStreptococcusconstellatus,Citrobac- eravacyclinegroupand2patients(0.7%)intheertapenem
terfreundii,Klebsiellapneumoniae,andBacteroidesthetaio- group,andphlebitiswasrecordedfor8patients(3.0%)inthe
taomicron.Thebaselinepathogensforwhichtheincidenceof eravacyclinegroupand1patient(0.4%)intheertapenem
favorableresponseswasatleast10%lowerintheeravacy- group.Thenumberandpercentageofpatientswhoexperi-
clinetreatmentgroupcomparedwiththeertapenemtreat- encedseveretreatment-emergentadverseevents,including
ment group included Enterobacter cloacae, Bacteroides life-threateningandfatalevents,weresimilarbetweenboth
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Research OriginalInvestigation EravacyclinevsErtapeneminComplicatedIntra-abdominalInfections
Table4.ClinicalCureattheTOCVisitbyBaselinePathogen(Micro-ITTPopulation,With≥10Patients/Isolate)
No./TotalNo.(%)
Eravacycline,1.0mg/kgEvery12h Ertapenem,1.0gEvery24h
BaselinePathogena (n=220) (n=226)
Gram-negativeaerobes 155/182(85.2)b 162/186(87.1)
Enterobacteriaceae 142/168(84.5) 147/171(86.0)
CEPH-Rc 18/20(90.0) 18/22(81.8)
ConfirmedESBL 19/21(90.5)d 15/18(83.3)e
CP-Rf 1/1(100.0) 4/5(80.0)
Confirmedcarbapenemase 1/1(100.0)g 0/1(0.0)h
MDRi 14/16(87.5) 11/12(91.7)
Escherichiacoli 109/127(85.8) 112/132(84.8)
Klebsiellapneumoniae 16/18(88.9) 19/23(82.6)
Proteusmirabilis 13/14(92.9) 10/11(90.9)
Gram-negativeaerobes(other) 37/44(84.1) 32/34(94.1)
Pseudomonasaeruginosa 15/18(83.3) 18/20(90.0)
Acinetobacterspecies 8/8(100) 6/6(100)
CEPH-Rc 8/8(100) 5/5(100)
ConfirmedESBL 5/5(100)j 1/1(100)k
CP-Rf 3/3(100) 4/4(100)
Confirmedcarbapenemase 2/2(100)l 4/4(100)m
MDRi 7/7(100) 4/4(100)
Stenotrophomonasmaltophilia 1/3(33.3) 1/1(100)
Gram-positiveaerobes 101/117(86.3) 105/120(87.5)
Streptococcusspecies 58/65(89.2) 54/64(84.4)
Enterococcusfaecalis 16/23(69.6) 21/26(80.8)
Enterococcusfaecium 13/16(81.3) 26/30(86.7)
Anaerobes 88/106(83.0) 94/107(87.9)
Bacteroidesfragilis 39/44(88.6) 38/42(90.5)
Bacteroidesovatus 13/19(68.4) 15/17(88.2)
Bacteroidesthetaiotaomicron 23/26(88.5) 17/20(85.0)
Abbreviations:CEPH-R,cephalosporin-resistant;CLSI,ClinicalandLaboratory dOneormore:CTX-M-1-like,CTX-M-14,CTX-M-15-like,CTX-M-3-like,
StandardsInstitute;CP-R,carbapenem-resistant;ESBL,extended-spectrum CTX-M-55/79,OXA-1/30,SHV-1,SHV-11,SHV-30,orTEM-1.
β-lactamases;ITT,intent-to-treat;MDR,multidrugresistance;TOC,test-of-cure. eOneormore:CTX-M-1-like,CTX-M-15-like,CTX-M-3-like,OXA-1/30,SFO-1-like,
aClinicalresponseisbasedontheSurgicalAdjudicationCommitteeassessment. SHV-1,SHV-11,SHV-12,orTEM-1.
Patientswiththesamepathogenfrommorethan1specimenwerecounted fCP-R=carbapenem-resistantaccordingto2015CLSIbreakpoints.
onlyonceforthatpathogen.Patientswerecountedonlyonceintheoverall
gKPC-2.
tabulationofgram-negativeaerobes,gram-negativeanaerobes,and
gram-positiveaerobes.Patientsarecountedonlyoncefortheoverall hOXA-48.
tabulationofEnterobacteriaceae,Bacteroidesspecies,andStreptococcus iMultidrugresistantaccordingtomodifiedEuropeanSocietyofCritical
species. Microbiologycriteria.18
bResultsarepresentedasNo./totalNo.(%),whereNo.=patientswith jGES-11orPER-1.
favorableoutcomes,totalNo.=totalpatientswiththerespectivepathogen, kGES-11.
and%=No./totalNo.×100.ForCEPH-R,CP-R,andMDRresults,total
No.=totalpatientswithanisolatewitharesistantphenotypethatreceived lOXA-23orOXA-72-like.
furthertestingfordeterminationofβ-lactamaseresistancemechanism mOXA-23,OXA-72-like,orVIM-2.
(genotype).
cCEPH-R=third-/fourth-generationcephalosporin-resistantaccordingto2015
CLSIbreakpoints.
treatmentgroups:15(5.6%)foreravacyclineand16(6.0%)for boththeFDAandEMAprimaryendpointsofnoninferiorclini-
theertapenem. calefficacyvsertapenem.
Thepatientsenteredinthistrialweresomewhatdiffer-
entfromthosein2trialsperformedin2015and2016.We
limitedthepercentageofpatientswithappendicitis,an
Discussion
infectionwithhighcurerates,to30%.Inthetrialwith
InthisphaseIIItrialcomparingeravacyclinewithertapenem ceftolozane/tazobactam,46%ofthepatientshadappendici-
forcomplicatedintra-abdominalinfections,eravacyclinemet tiswithacurerateof96%.19Intheceftazidime/avibactam
230 JAMASurgery March2017 Volume152,Number3 (Reprinted) jamasurgery.com
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EravacyclinevsErtapeneminComplicatedIntra-abdominalInfections OriginalInvestigation Research
trial,41%ofpatientshadappendicitiswithasimilarlyhigh callymultifactorial,primarilydrivenbybackgrounddisease
successrate.20 andsepticshock.
Therehasbeenconsiderableimprovementinclinical Wenotedhighsuccessratesinthisstudywithorganisms
outcomesintrialsconductedinthepastdecadecompared knowntoberesistanttooneortheotheragentusedinthis
withthosereported10ormoreyearsago.Forexample,ina study.Thisisofparticularrelevanceforertapenemanderava-
2003study,245of311patientstreatedwithertapenem cyclineactivityagainstPaeruginosaandforertapenemagainst
(79.3%)werecured,aswere232of304(76.2)treatedwith Acinetobacter.Thisphenomenonisobservedinmostrandom-
piperacillin/tazobactam.19Wenotedaconsiderableincrease izedclinicaltrialsincIAI.Themostcommonexplanationisthat
intheuseoflaparoscopicandpercutaneousprocedures thesourcecontrolprocedurereducestheinoculumdensity
compared with open operations in previous trials. The substantially,sothatongoinginvasiveinfectionistermi-
movementtolessinvasiveprocedureshasbeenassociated nated.However,multipleplacebo-controlledtrialsinperfo-
withreducedtreatmentfailure.21-23 ratedappendicitisdemonstratesignificantbenefitoforganism-
Source control, the physical steps taken to drain specifictherapy.25Anotherpossibilityisthatinpolymicrobial
abscessesandcorrectanyunderlyingintestinaldiscontinuity, infections,therequirementformicrobialsynergymaymean
isanessentialelementoftreatment.24Becauseofthedepen- curerateswouldbeincreasedifonlypartoftheinfectingflora
dencyofinfectionratesonthetypeofprocedureperformed werekilled.Tosupportthis,wenotedthat97%ofcaseshar-
andbecausetheprocedureistypicallydictatedbytheorgan boringPaeruginosaalsohadcoinfectingsusceptibleisolates.
oforigin,wewouldliketohighlighttheimportanceofdocu- Itwouldappearthatthebestevidenceforanagent’sactivity
mentingtheorganoforiginratherthanonlythepresenceof againstaspecificorganismisthedemonstrationofclinical
abscess/peritonitisbecausethismayobscuretheclinical eradicationcombinedwithinvitrosusceptibility.Thecauses
detailsofinfectionandthesourcecontrolprocedureper- offailureweresimilarbetweenthetreatmentgroupsandare
formed. consistentwithfindingsinclinicalpracticeandinothertrials.
Themicrobiologyencounteredinthistrialissimilarto
thatseeninotherclinicaltrialsincIAI.Mostinfections Limitations
(>90%)werepolymicrobial,andgram-negativefacultativeor TrialsofantimicrobialtherapyincIAIsareatriskofconfound-
aerobicorganismswereisolatedin82%ofpatients.Clinical ingbythevariousfactorsthataffecttheoutcome.Thesefac-
cureratesbyorganismwereequivalentbetweeneravacycline torsincludepatientswithvaryingpremorbidconditions,clini-
andertapenemacrossalltypesoforganisms.Patientswithceph- caldetailsoftheacutediseaseprocessvaryingsignificantly
alosporin-resistantisolatesandthelargesubsetofthose intheirprognosticimportance,andperioperativecareprac-
expressingESBLswerecuredatratesequivalenttocephalo- ticesthatmayalteroutcomesifnotstandardized.Finally,the
sporin-susceptibleandnon-ESBL–producingorganisms. timingandnatureoftheprocedureperformedmayvarywithin
ThepresenceofESBLsin9%ofthepatientsisofconcern. specificdiseasestates.Theseindividualoutcomedetermi-
Placebo-controlledrandomizedclinicaltrialshavedemon- nantsmayhavestrongereffectsthantheantimicrobialagent
stratedacriticalroleforantibioticstargetingtherangeof givenandthusmayconfoundthestatisticalanalysis.Toavoid
organismsencounteredinthesemixedflorainfections,with theseproblems,thisstudyenrolledalargenumberofpa-
asubstantialeffectsize.16Whether,inthepresenceofresis- tientsandlimitedthewiderangeofpremorbidconditionssuch
tance,empiricaltreatmentactiveagainstthegram-negative asterminalcancerandotherlife-threateningdiseasesal-
organismsresistanttoβ-lactamspriortoincisionwouldpro- lowedforstudyentry,controlledthetimingofstudydrugini-
videevenlowersurgicalsiteinfectionsisnotknown.For tiationtomaximizeeffectiveness,andusedobjectiveend
90% of the patients, perioperative antibiotics were points,suchasdeathorsurgicalsiteinfection,astheout-
β-lactams,andstudy-driventherapywasnotgivenuntilthe comedeterminants.
postoperativeperiod.Giventhesmallnumbersoffailures
withESBLs,acaseforempiricaltreatmentfortheseisolates
cannotbemadeuntilstudieswithhigherbackgroundESBL
Conclusions
ratesaredone.
Thisandotherprotocolsexcludepatientswithrapidlyfa- Inthisstudy,intravenouseravacycline,1.0mg/kgevery12
talbackgrounddiseaseorsepticshock.Theoutcomeofinter- hours,wasfoundtobenoninferiortoertapeneminpatients
estistheabilityofthestudyagentstoresolvethelocalinfec- withcIAIs.Themicrobiologyandpatientsencounteredinthis
tionandpreventrecurrentsurgicalsiteinfections.Mortality trialwererepresentativeofthebroadergroupofpatientsseen
confoundsanantibioticefficacystudybecausedeathistypi- inclinicalpracticewithsuchinfections.
ARTICLEINFORMATION responsibilityfortheintegrityofthedataandthe Criticalrevisionofthemanuscriptforimportant
AcceptedforPublication:July26,2016. accuracyofthedataanalysis. intellectualcontent:Evans,Slepavicius,Lee,Tsai,
Conceptanddesign:Solomkin,Slepavicius,Lee, Sutcliffe,Horn.
PublishedOnline:November16,2016. Horn. Statisticalanalysis:Slepavicius,Lee,Tsai.
doi:10.1001/jamasurg.2016.4237 Acquisition,analysis,orinterpretationofdata: Administrative,technical,ormaterialsupport:
AuthorContributions:DrsSolomkinandHornhad Solomkin,Evans,Slepavicius,Tsai,Sutcliffe,Horn. Solomkin,Evans,Sutcliffe,Horn.
fullaccesstoallofthedatainthestudyandtake Draftingofthemanuscript:Solomkin,Evans,
Slepavicius,Sutcliffe,Horn.
jamasurgery.com (Reprinted) JAMASurgery March2017 Volume152,Number3 231
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Research OriginalInvestigation EravacyclinevsErtapeneminComplicatedIntra-abdominalInfections
ConflictofInterestDisclosures:DrSolomkin withcarbapenem-resistantKlebsiellapneumoniae infectionsinadultpatientsbasedonpoint
reportspersonalfeesandnonfinancialsupport infection.BMCInfectDis.2013;13:80. prevalencemeasurements.AmJInfectControl.
fromTetraphasePharmaceuticalsIncduringthe 6.FrakkingFN,RottierWC,Dorigo-ZetsmaJW, 2016;44(5):500-506.
conductofthestudyandpersonalfeesfromCubist etal.Appropriatenessofempiricaltreatmentand 17.SolomkinJS,RistagnoRL,DasAF,etal.Source
Pharmaceutical,Merck,Pfizer,GlaxoSmithKline, outcomeinbacteremiacausedby controlreviewinclinicaltrialsofanti-infective
andMelintaoutsideofthesubmittedwork.Dr extended-spectrum-β-lactamase-producing agentsincomplicatedintra-abdominalinfections.
EvansreportsgrantsfromTetraphaseduringthe bacteria.AntimicrobAgentsChemother.2013;57(7): ClinInfectDis.2013;56(12):1765-1773.
cPohnadrmucatcoefutthicealsatunddyMaenrdckgroaunttssidfreoomftChuebsisutbmitted 3092-3099. 18.MagiorakosAP,SrinivasanA,CareyRB,etal.
work.DrSlepaviciusreportsgrantsfromTetraphase 7.PotronA,PoirelL,NordmannP.Emerging Multidrug-resistant,extensivelydrug-resistantand
PharmaceuticalsIncforhisroleasPrincipal broad-spectrumresistanceinPseudomonas pandrug-resistantbacteria:aninternationalexpert
Investigator.DrsSutcliffe,Horn,andTsaiandMr aeruginosaandAcinetobacterbaumannii: proposalforinterimstandarddefinitionsfor
Marsharefull-timeemployeesofTetraphase.No Mechanismsandepidemiology.IntJAntimicrob acquiredresistance.ClinMicrobiolInfect.2012;18
otherdisclosuresarereported. Agents.2015;45(6):568-585. (3):268-281.
Funding/Support:Thisstudywassponsoredby 8.ViehmanJA,NguyenMH,DoiY.Treatment 19.SolomkinJ,HershbergerE,MillerB,etal.
TetraphasePharmaceuticalsInc. optionsforcarbapenem-resistantandextensively Ceftolozane/tazobactamplusmetronidazolefor
drug-resistantAcinetobacterbaumanniiinfections. complicatedintra-abdominalinfectionsinaneraof
RoleoftheFunder/Sponsor:Thesponsor Drugs.2014;74(12):1315-1333. multidrugresistance:resultsfromarandomized,
pworrhgoiavcnihdizweadatsitohgneefnarueotrmhatotehrdsewboyirtithghitnehacelocCnaltisnreaiccraetlprSeotsruetdafyorcrRhmesport, 9D.önNhgöufyeernAF,,WSitlasroonstDaNA.LT,eAtrraecnyzcSli,nSeoahnmtiebnioDti,csand dDoisu.b2l0e1-b5;li6n0d(,1p0h)a:1s4e632t-r1i4a7l1(.ASPECT-cIAI).ClinInfect
andcontainedallofthenecessaryinformationon resistancemechanisms.BiolChem.2014;395(5): 20.MazuskiJE,GasinkLB,ArmstrongJ,etal.
thedesignandconductofthestudy.Thesponsor 559-575. Efficacyandsafetyofceftazidime-avibactamplus
hadnoroleinthecollection,management,analysis, 10.ZhanelGG,CheungD,AdamH,etal.Reviewof metronidazolevsmeropeneminthetreatmentof
andinterpretationofthedata;preparation,review, eravacycline,anovelfluorocyclineantibacterial complicatedintra-abdominalinfection:resultsfrom
orapprovalofthemanuscript;anddecisionto agent.Drugs.2016;76(5):567-588. arandomized,controlled,double-blind,phase3
submitthemanuscriptforpublication. 11.SutcliffeJA,O’BrienW,FyfeC,GrossmanTH. program.ClinInfectDis.2016;62(11):1380-1389.
AdditionalContributions:AngieSway,BA,Oasis Antibacterialactivityoferavacycline(TP-434), 21.BroderickRC,FuchsHF,HarnsbergerCR,etal.
GlobalIncandJohnsHopkinsUniversity,and anovelfluorocycline,againsthospitaland Thepriceofdecreasedmortalityintheoperative
KimberleySeverin,MS,JohnsonandJohnson, communitypathogens.AntimicrobAgents managementofdiverticulitis.SurgEndosc.2015;29
contributedtothewritingandrevisionofthe Chemother.2013;57(11):5548-5558. (5):1185-1191.
manuscript.Nocompensationfromafunding 12.SolomkinJS,RameshMK,CesnauskasG,etal. 22.SolomkinJS,YellinAE,RotsteinOD,etal;
sponsorwasreceivedbyeithercontributor. Phase2,randomized,double-blindstudyofthe Protocol017StudyGroup.Ertapenemversus
efficacyandsafetyoftwodoseregimensof piperacillin/tazobactaminthetreatmentof
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