w w w . e l s e v i e r . c o m / l o c a t e / b j i d
The
Brazilian
Journal
of
INFECTIOUS
DISEASES
Original
article
Clinical
and
economic
impact
of
generic
versus
brand
name
meropenem
use
in
an
intensive
care
unit
in
Colombia
Karen
Ordó ˜nez
a,
Max
M.
Feinstein
b,c,e,
Sergio
Reyes
b,e,
Cristhian
Hernández-Gómez
b,e,
Christian
Pallares
b,d,e,
María
V.
Villegas
b,d,e,∗aE.S.E.HospitalUniversitarioSanJorge,Pereira,Colombia
bCentroInternacionaldeEntrenamientoeInvestigacionesMédicas(CIDEIM),Cali,Colombia cCaseWesternReserveUniversity,Cleveland,UnitedStates
dCentroMédicoImbanaco,Cali,Colombia
eGrupodeInvestigaciónenResistenciaAntimicrobianayEpidemiologíaHospitalaria,UniversidadElBosque,Bogotá,Colombia.
a
r
t
i
c
l
e
i
n
f
o
Articlehistory:
Received17March2019 Accepted16June2019 Availableonline22July2019
Keywords: Genericdrugs Meropenem Mortality Costs Criticalcare
Gramnegativebacteria
a
b
s
t
r
a
c
t
Background:Recentstudiessuggestthatsustaineduseofgenericantibioticsmaybe asso-ciatedwithclinicalfailureandemergenceofantibacterialresistance.Thepresentstudy wasdesignedtodeterminetheclinicaloutcomebetweentheuseofgenericmeropenem (GM)andbrand-namemeropenem(BNM).Additionally,thisstudyevaluatedtheeconomic impactofGMandBNMtodetermineiftheformerrepresentsacost-effectivealternativeto thelatter.
Methods:PatientstreatedbetweenJanuary2011andMay2014receivedGMwhilepatients treatedbetweenJune2014andMarch2017receivedBNM.Mortalitywascomparedbetween groups.Totalinfectioncostwasdefinedbythecostofantimicrobialconsumption,lengthof stay,andlaboratoryandimagingexamsuntilinfectionresolution.
Findings: Atotalof168patientswereincluded;survivalrateforthe68 patientstreated withGMwas38%comparedto59%inthepatientstreatedwithBNM.Multivariate anal-ysisshowedthatthevariablesmoststrongly-associatedwithmortalitywerecardiovascular disease(OR18.18,95%CI1.25–262.3,p=0.033)andtreatmentwithgenericmeropenem(OR 18.45,95%CI1.45–232.32,p=0.024).Ontheotherhand,totalinfectioncostdidnotshowa significantdifferencebetweengroups(BNM$10,771vs.GM$11,343;p=0.91).
Interpretation:ThepresentstudysuggeststhatpatientstreatedwithGMhaveariskofdeath 18 timeshighercomparedto thosetreated withBNM. Furthermore,economic analysis showsthatGMisnotmorecosteffectivethanBNM.
∗ Correspondingauthorat:Research GrouponAntimicrobialResistanceandHospitalEpidemiology-RAEH,UniversidadElBosque,
Bogotá,Colombia.Mailingaddress:Cra9#131A-02,LabdeInvestigacion2Piso,Bogotá,Colombia.
E-mailaddresses:[email protected](K.Ordó ˜nez),[email protected](M.M.Feinstein),[email protected](S. Reyes),[email protected](C.Hernández-Gómez),[email protected](C.Pallares),[email protected](M.V.Villegas).
https://doi.org/10.1016/j.bjid.2019.06.010
1413-8670/©2019SociedadeBrasileiradeInfectologia.PublishedbyElsevierEspa ˜na,S.L.U.ThisisanopenaccessarticleundertheCC BY-NC-NDlicense(http://creativecommons.org/licenses/by-nc-nd/4.0/).
Summary: Morestudiesmeasuringclinicaloutcomesareneededtoconfirmtheclinical equivalenceofbrand-nameversusgenericantibiotics,notonlyformeropenembutalsofor othermolecules.
©2019SociedadeBrasileiradeInfectologia.PublishedbyElsevierEspa ˜na,S.L.U.Thisis anopenaccessarticleundertheCCBY-NC-NDlicense(http://creativecommons.org/
licenses/by-nc-nd/4.0/).
Introduction
Thegenericmedicationcontainsthesamecomponentsand specificationsas the brand-namemedication.InColombia, genericmedicationsareavailableforpurchase10yearsafter thecommercial patentofthe originalbrand-name medica-tionexpires.Genericmedicationsmustcomplywithavariety of conditions to be approved for commercial use. Broadly speaking,genericmedicationsmustcontainthesame quan-titative and qualitative composition of active ingredients compared to their brand-name counterpart. Furthermore, the pharmaceutical presentation must be similar to their respectivebrand-namecounterpart withregards to formu-lations (e.g., parenteral, enteral, etc.), safety profile, and pharmacokinetics.1Theprescriptionofgenericmedications isconsideredoneofthemosteffectiveapproachesfor reduc-ingcostandincreasingglobalaccesstofirst-linemedication forthetreatmentofdiverseinfections.2,3
Manycountrieshaveprogressivelyopenedtheirmarkets togenericmedications.In2010,genericantibiotics(GA) rep-resentedmorethantwo-thirdsoftheglobalconsumptionof medications.3IntheUnitedStates,genericmedicationsmade upto 63%oftotalprescriptions in2007,4 whileinEngland thatnumberwas83%in2008.5Thegenericmedication mar-kethaslikewiseexpandedinotherdevelopedcountriessuch asJapan.2
Recently,theuseofgenericmedicationshascaused contro-versy,particularlyinthecaseofGA.Ithastraditionallybeen consideredthatGAs,principallyinparentalform,havethe sameefficacyasbrand-nameantibiotics(BNA).2,3,6–9However, severalstudieshavequestionedtheclinicaleffectivenessof GAs,reportingissueslikeclinicalfailureoremergenceof bac-terialresistanceassociatedwiththesustaineduseofGas.3,5,7,8 Antibiotic resistance has also been related to a signifi-cantuseofGAsfollowingtheirreleaseintothedrugmarket. Thiscollateraldamagehasbeen demonstratedinGermany andDenmarkwhereuseofgenericquinolonesgenerateda disproportionateincreaseinitsuse,followedbyanincrease in resistance levels from 7.7% to 25% and 0.8% to 4%, respectively.10,11 This phenomenon hasalso been reported inColombiawheretheuse of-lactams hassurpassedthe 90thpercentileofthedefineddailydose,considerablymore thanhasbeenreportedinothercountries.12–14Onanational level, someantibioticsare consumedmore thanothers, as isthecasewithmeropenem giventhe readyavailabilityof itsgenericversion.Meropenemprovidesadequatecoverage against Pseudomonas aeruginosa and is considered first-line treatmentforanumberofcomplicatedinfectionsincluding intra-abdominalinfections,bacterialmeningitis,bloodstream infections, nosocomial pneumonia, septicemia, and febrile neutropenia.15
On the other hand, the characteristics of GAs can be affectedbyavarietyofelements,suchasactiveingredient, bioequivalence,impurities,additives,andexcipients.Manyof theseelementsdependonthemanufacturingprocess,which can vary among GAs and BNAs. In a country where GAs represent alarge portion ofmedications consumed dueto limited resources, the therapeuticefficacy ofGAs needsto beevaluated.Thiswillcontributetogreaterconfidenceinthe prescriptionofGAs,aswellasprovideabetterunderstanding ofpossibledeleteriouseffectsrelatedwiththeiruse.
Keepinginmindthecurrentuncertaintiesregarding pos-sible differences between GAs and BNAs, this study was designed to determine the clinical impact associatedwith the use ofgeneric versus brand-namemeropenem for the treatmentofinfectionscausedbyGram-negativebacteria sus-ceptibletocarbapenems.Thisstudyevaluatedpatientswho werehospitalizedintheintensivecareunit(ICU)ofatertiary carehospitalinColombia.
Materials
and
methods
Studydesign
Thiscohort study comparedpatients who receivedgeneric and brand-name meropenem. The group that received genericmeropenemincludedpatientshospitalizedintheICU betweenJanuary2011andMay2014inatertiarycare hospi-talinPereira,Colombia.Theintroductionofthegenericwas partofthehospitaladministrationstrategytoreducecosts.In contrast,patientshospitalizedfromJune2014toMarch,2017 inthesameICUweretreatedwithbrand-namemeropenem basedonanewpolicyofbuyingbrandantibioticsagain;these patientsconstitutethebrand-namecohort.
Duringbothtimeperiodsofthestudy,theinfection con-trolsurveillancedidnotchangenorthepreventionstrategies implementedbytheInfectiousDiseaseCommittee.Also,the dosing,infusionandtimeoftreatmentformeropenemwas thesamebasedontheinstitutionalantimicrobialguidelines inbothgroups.
Inclusion criteria forthe study were age over 18 years, patients hospitalized in the ICU, an infection caused by meropenem-susceptible Gram-negative bacteria, and treat-mentwithmeropenem.Patientswereexcludedifanyofthe followingcriteriaweremet:deathwithinthefirst72hof ini-tiationofmeropenemtherapy,aconcomitantinvasivefungal infection,concomitantprescriptionoffourormoredosesof antibioticswiththesameantibacterialactivityasmeropenem, andincompletepatientrecords.
Forsamplesizecalculation,mortalityinColombianICUs associated to intrahospital infections was assumed to be
25.6%.16–20 This proportion was considered for unexposed patients, that is, those patients who received brand-name meropenem.Thedifferencebetweentheproportionamong exposed and unexposed patients was considered; for the exposed patients who received generic medication, an increaseinmortalityof68.5%21 was assumed.Astatistical powerof80%andaconfidencelevelof95%wereused,with anexposed/unexposedratioof1andalossof10%.The calcu-latedsamplesizewas140patientsineacharm,totaling280 patients.Exposedandunexposedwere matchedforage(in 10-yearranges)andfortypeofinfection.Samplingwas per-formedbyincludingnon-probabilisticpatientsconsecutively. SamplesizewascalculatedintheprogramEPIDATversion3.1. Becausewewereunabletocompletetheexpectedsamplesize, ourpowerdecreased26.6%.
The study was conducted under the appropriate local and international ethics guidelines and approved by the institutional review board of the International Center for Training and Medical Research (CIDEIM, per its abbrevia-tion in Spanish) and the participating institution. CIDEIM deemed that informed consent was not necessary for the studygiventhatitsdesignentailedminimalriskforthe sub-jects.
Datacollection
Patient data relevant to the study was retrieved from the hospital’selectronicmedicalrecordsystemandrecordedon writtendatacollectionforms.Datacollectedincludedpatient demographicinformation,hospitaladmissionanddischarge dates,ICUadmissionand dischargedates,clinicaland lab-oratory data needed to calculate Sequential Organ Failure Assessment(SOFA)score,comorbidities,infectiontype, sus-ceptibilityprofileoftheinfectingorganism,antibioticdoses receivedduringtheinfectionepisode,clinicalandlaboratory testsorderedbetween theinfection episodeand discharge, andsurvivalstatusupondischarge.
Statisticalanalysis
In the descriptive statistical analysis, proportions were determined for qualitative variables, and mean or median calculatedasdeterminedbythedistributionofquantitative variables.The oddsratio for mortalityassociated withthe useofgenericand brand-meropenemwas computedusing two-by-two contingency tables. Chi square or Fisher exact testswereusedforcomparisonsofqualitativevariables.For quantitative variables, parametric or non-parametric tests wereuseddependingonwhetherdistributionwasnormalor not.Survivalanalysisfor7-and28-daysurvivalbothcohorts werecomparedusingLog-ranktest,adjustedforseverityand adequate therapy. Both cohorts were matched forage and type of pathology. In the multivariate analysis, odds ratio wascalculatedusinglogisticregressionwithadjustmentfor the matching variables, and a conditional logistic regres-sionwas performed fordeath as anoutcome. All possible modelsincludedpairedvariables,startingwiththosewitha p-value<0.20inthe univariateanalysis.Inthemultivariate analysis, p-value <0·05 was considered statistically signifi-cant.
Economicanalysis
Thecostofcareforpatientswithinfectionsthatwereselected forthestudycorrespondedtothesumoftheantibiotic con-sumption and length of stay until infection resolution. A partialeconomic assessmentwas carried out using micro-costingtechniquesasawayofdeterminingthemagnitudeof theresourcesspent.Allocationofcostsforeachresourcewas basedonareferencecostandadjustedbytheinflationrate basedontheColombianmanualdocumentforcosts.22 Incre-mental cost-effectiveness ratio (ICER), which is a measure ofcost-effectivenessforagivenintervention,wascalculated usingdecisiontreemodel.Survivalwasdefinedasthe clini-caloutcomeforeffectiveness,whileeconomicoutcomewas definedasthetotalinfectioncostperpatient.
Results
Clinicalimpact
A total of 1289 patients received meropenem during the studyperiod,318patientsreceivedgenericmeropenemand 971 received brand-name meropenem.Of the 318 patients treated with genericmeropenem, 68 (21.3%) met inclusion criteriaforthestudy.Ofthe971patientstreatedwith brand-name meropenem, 100 (10.3%) met these criteria. Thus, a totalof168patientswereincludedinthestudy.Demographic characteristicssuchasSOFAscore,durationofantibiotic treat-ment,timeofinfusionanddosingofmeropenem,aswellas the microorganismscausingtheinfection werecomparable amonggroups(Table1).Regardinginfection type,themost commonwasventilator-associatedpneumoniainthegeneric group(23%vs.8%,p=0.005)andabdominalinfectioninthe brand-namegroup(13%vs.34%,p=0.004).Ontheotherhand, the brand-namegroup had a higher prevalence of comor-biditiessuchastype2diabetes(15%vs. 28%,p=0.043)and cardiovasculardisease(23%vs.38%,p=0.049).Also,historyof hospitalizationinthethreemonthspriortohospital admis-sionwasmorecommoninthebrand-namegroup(53%vs.72%, p=0.011).
WecategorizedtheSOFAinlowerandhigherthan10,since theSOFAgreaterthan10isassociatedwithamortalityofmore than40%.Onday7and28therewerenodifferencesin mortal-itybyseverity.Incontrast,therewashighermortalityatday7 and28,inpatientsusinggenericmeropenem(Fig.1).
Mortalitywasgreaterinthegenericgroup(62%vs.41%, p=0.008); univariateanalysis was performedto assess risk factorsassociatedwithmortality.Statisticallysignificant vari-ables were agegreater than 73 (RR4.98,95% CI1.31–18.96, p=0.018),history ofcardiovascular disease(RR 2.53,95% CI 1.23–5.26, p=0.02), presenceofcentral venouscatheter (RR 2.92,95%CI1.07–8.74,p=0.02),ventilator-associated pneumo-nia(RR6.43,95%CI1.99–26.9,p=0.000),andtreatmentwith genericmeropenem (RR2.32,95% CI1.18–4.59,p=0.008),as showninTable2.
Asbothgenericandbrand-namemeropenemgroupswere comparablebyageandcomorbiditiesinpreviousanalyses,the multivariateanalysiswasadjustedforSOFA,GLASGOWand
Table1–Univariateanalysis.
Variable Genericmeropenemgroup Brandnamemeropenemgroup p-value
n=68(41%) n=100(59%) Sex 0.318 Male 42(62%) 54(54%) Female 26(38%) 46(46%) Age(years) 0.440 18–28 7(10%) 6(6%) 29–39 7(10%) 16(16%) 40–50 7(10% 11(11%) 51–61 12(18%) 24(24%) 62–72 14(21%) 19(19%) >72 21(31%) 24(24%) Age 58.6(SD±19.7) 56.47(SD±17.45) Previoushospitalization 36(53%) 72(72%) 0.011 Comorbidities Diabetes 10(15%) 28(28%) 0.043 Pulmonarydisease 8(12%) 16(16%) 0.441 Immunosuppression 3(4%) 7(7%) 0.742 Neurologicdisease 7(10%) 2(2%) 0.032 Renaldisease 6(9%) 4(4%) 0.319 Liverdisease 1(1%) 1(1%) 1 Cardiovasculardisease 16(23%) 38(38%) 0.049 Cancer 5(7%) 3(3%) 0.271
SequentialOrganFailureAssessment(SOFA)score 0.180
0–6 10(40%) 17(52%)
7–9 7(28%) 11(33%)
10–12 6(24%) 5(15%)
13–14 2(8%) 0(0%)
SOFA 7.72(SD=2.96) 6.69(SD=2.59)
GlasgowComaScale(GCS)score 0.660
Mild 43(65%) 54(69%) Moderate 7(11%) 6(8%) Severe 16(24%) 18(23%) Glasgow 12.37(SD±3.64) 12.11(SD±4.25) Invasivedevices Orotrachealtube 62(91%) 85(85%) 0.235
Centralvenouscatheter 60(88%) 83(83%) 0.349
Foleycatheter 59(87%) 86(86%) 0.887
Infectiontype
Bloodstreaminfection 29(43%) 54(54%) 0.149
Ventilator-associatedpneumonia 16(23%) 8(8%) 0.005
Urinarytractinfection 9(13%) 10(10%) 0.516
Skinandsofttissueinfection 3(4%) 4(4%) 1
Meningitis 2(3%) 1(1%) 0.565
Intraabdominalinfection 8(13%) 33(34%) 0.004
Dosingintervalofmeropenem 0.290
6hours 1(2%) 1(1%)
8hours 60(88%) 94(94%)
12hours 7(10%) 3(3%)
24hours 0(0%) 2(2%)
Prolongedmeropeneminfusion 4(10%) 23(24%) 0.096
Timebetweencultureandinitiationofmeropenemtreatment 0.765
Immediate 26(38.2%) 19(73%)
24–72hours 10(14.7%) 1(4%)
>72hours 12(17.6%) 1(4%)
alreadyreceiving 1(1.4%) 0
Timebetweencultureandinitiationofmeropenem 18(SD±39.01) 43.7(SD±53.13) Daysoftreatmentwithmeropenem
<7days 1/49(2%) 0/14(0%) 0.778
7days 22/50(44%) 13/21(62%) 0.168
Ceftriaxone 16/51(31%) 9/23(39%) 0.514
Ciprofloxacin 18/53(34%) 6/22(27%) 0.572
Multidrugresistantbacteria 15(22%) 20(20%) 0.747
–Table1(Continued)
Variable Genericmeropenemgroup Brandnamemeropenemgroup p-value
n=68(41%) n=100(59%) Infectiousorganism Escherichiacoli 18(27%) 41(43%) Klebsiellapneumoniae 16(24%) 16(17%) Enterobacterspp. 7(11%) 5(5%) Proteusspp. 1(1%) 2(2%) Pseudomonasaeruginosa 8(12%) 18(19%) Serratiamarcescens 3(4%) 6(6%) Acinetobacterbaumannii 10(15%) 5(5%) Morganellamorganii 3(4%) 3(3%) Mortality 42(62%) 41(41%) 0.008
7-Day Life Analysis by SOFA SEVERITY (p = 0.64) 7-Day survival analysis by exposure (p =0,0054)
1.00 1.00 0.75 0.75 0.50 0.50 0.25 0.25 0.00 1.00 0.75 0.50 0.25 0.00 0 0 0 10 20 30 10 20 30 40 50 4 6 8 0 Brand-name meropenem Brand-name meropenem SOFA SCORE < 10 SOFA SCORE < 10
28-Day Survival analysis by SOFA severity (p = 0,83) 28-Day Survival analysis by exposure (p=0,0045) SOFA SCORE >/= 10 SOFA SCORE >/= 10 Generic Meropenem Generic Meropenem 2 4 6 analysis time analysis time analysis time analysis time 8 2 0.00 1.00 0.75 0.50 0.25 0.00
Fig.1–Lifecharts.
timeofadministrationofmeropenem.Exposureand cardio-vasculardiseasewerestatisticallysignificant.
Patientswhoreceivedgenericshad18-foldhigherriskof dying comparedwiththosewho receivedbrand-name(OR: 18.4595%CI:1.46–232)andpatientswithcardiovascular dis-easealsohad18-foldhigherriskofdyingcomparedwiththose whodidnothavethiscomorbidity(OR:18.195%CI:1.26–262). Inspiteofthewideconfidenceintervals,duethesmallsample size,theydidnotinclude1,withagoodstatisticalsignificance
(Table3).
Economicimpact
The total antimicrobialcost was lower in the brand-name groupascomparedtothegenericgroup($303vs.$588).The totalcostofICUstaywasalsolowerinthebrand-namegroup ($8,896 vs.$7,705).However,the totalcostofinfection was notsignificantlydifferentbetweengroups(brand-namecost $10,771vs.genericcost$11,343).
The ICERis ameasure ofcost-effectiveness for agiven intervention,whichinthiscaseisthechoiceofantibiotic.The
Survival Rate Total Infection
Cost Cost difference differenceSurvival
Brand-name Meropenem
(100)
Patients with Gram negative infections Generic Meropenem (68) 38% $11,343 USD $2,724 USD Incremental cost-effectiveness ratio (ICER) 59% $10,771 USD $572 USD 21%
Fig.2–Cost-effectivenessdecisiontreemodel.
ICERwasdefinedbythecostofobtainingoneadditional effec-tivenessunit(patientsurvival)was$2,724USDperICUstay whenchangingfrom brandname moleculetogeneric. The cost-effectivenessdecisiontreemodelisshowninFig.2.
Discussion
In this study, we compared critically ill patients treated withgenericversusbrand-namemeropenem.Results demon-stratedgreatermortalityinthegenericgroupandcomparable totalcostsforbothgroups.Historyofcardiovasculardisease wasalsofoundtobeanindependentriskfactorformortality. Incontrast,thebrand-namehadahigherprevalenceof comor-bidities and historyofhospitalization in thethree months priortohospitaladmission.
Meropenemisoneofthemostcommonly-usedantibiotics incriticallyillpatientsduetoitsbroad-spectrumbactericidal activityanditspharmacokineticcharacteristics.Thepresent studysuggestsclinicalsuperiorityofbrand-namemeropenem withsimilarcostsincare.Therearefewclinicalstudiesthat comparedclinicaloutcomeswithtreatmentofgenericversus brand-nameantibiotics.Moststudies havebeen conducted invitroandanimalmodels.23,24 Also,systematicreviewson theefficacy and qualityofGAs havenotbeen ableto con-cludetheirinferiorityinrelationtoBNAs,maybeinpartdue totheheterogenousnatureanddifferentend pointsofthe studiesincluded,whichprecludedadefinitiveconclusion.25 Furthermore,itisdifficulttohavethepossibilityofevaluating brandversusgenericmeropeneminthesamehospital,under thesameconditions,likewewereabletodoinourstudy.For exampleinThailand,astudycomparinggenericversus brand-namemeropeneminhospitalizedpatients,ofwhich60%had documented microbiological data and some were infected withmeropenem-resistantbacteria,didnotfindinferiorityof eithermolecule.24However,inourstudytheinclusioncriteria was meropenem susceptible Gram-negative bacteria, elim-inating the possibility that resistance could interfere with outcomeascertainmentinthetwogroups.Another Colom-bian prospective cohort study that included 1015 patients withnosocomialinfectionsshowedinmultivariateanalysis a risk ofdeath almost two-foldhigher inpatients treated withGAscomparedtopatientstreatedwithBNAs(HR=1.91; 95%CI=1.43–2.55).21
SeveralstudiesledbyVesgaetal.havecomparedGAsand BNAsusinginvivomodels.Oneofthesestudiesusingthree differentbrandsofgenericvancomycinshowedlowerinvivo effectivenesscomparedtobrand-namevancomycindespite similaritiesofchemicalequivalenceandpotency.This differ-ence was statisticallysignificant and independent ofroute ofadministrationordoses.7 Furthermore,Vesgaetal.have shown difference inefficacy withother antibiotics, includ-ing meropenem,inwhichapharmacologicequivalencedid nottranslateintotherapeuticequivalenceinanimalinfection models.9Inthisstudy,theauthorsproposedthatdifferences inmeropenemefficacymightbesecondarytotrisodium com-poundsthatincreasesusceptibilityinthefaceofhydrolysis withintheorganism. Finally,Vesgaetal.alsoevaluatedthe impactofGAuseonbacterialsusceptibilityprofiles.8An ani-mal model was used to evaluate the resistance profile of StaphylococcusaureusinthefaceofsuccessivecyclesofGAand BNA.Itwasobservedthatgenericvancomycinprogressively selectedsubpopulationsofresistantbacteria,confirmingthe effectofsuboptimalbactericidalactionofGAon microorgan-ismsusceptibility.IncontrasttotheVesgaetal.findings,some authors likeLouieetal.and Hadwigeretal.havenotbeen abletoreplicatetheseresults.26,27Irrespectiveofthe contra-dictoryfindingswithanimalmodels,ourstudyresultsshowa statisticallysignificantdifferenceintheclinicaloutcomes.
Another keypointisthe therapeuticindicationsforGA. In the U.S., the Food and Drug Administration therapeu-ticindicationsforgenericandbrand-namemeropenem are identical.However,theColombianNationalInstituteofFood andDrugSurveillanceAgency(INVIMAinSpanish)has rec-ommendedonlybrand-namemeropenemforthetreatment offebrileneutropeniarathergeneric meropenem.Likewise, INVIMArecommendsonlybrand-namevancomycinforthe treatment of pneumonia, sepsis, or meningitis caused by penicillin-resistantStreptococcuspneumoniae;differenceinthe therapeutic indications between the GA versus the BNAs raisesconcernswhether GAscanbeprescribedinall kinds ofpatients,especiallywhencriticallyill.
This study isdifferent from other studiesregarding the clinicaloutcomesbetweengenericversusbrand-name antibi-otics. First, the selected study population was limited to criticallyill patients. Thispopulationwasselected because their conditions demand that antibiotics used have good
Table2–Bivariateanalysis.
Variable Relativerisk(95%CI/p-value)
Sex 0.72(0.37–1.38/p=0.285) Age 18–28 (Referencegroup) 29–39 0.47(0.10–2.34/p=0.359) 40–50 1.80(0.40–8.07/p=0.443) 51–61 2.51(0.65–9.67/p=0.180) 62–72 2.39(0.61–9.33/p=0.210) 73+ 4.98(1.31–18.96/p=0.018) Comorbidities Diabetes 1.79(0.88–4.03/p=0.119) Pulmonarydisease 1.25(0.48–3.30/p=0.614) Immunosuppression 1.03(0.23–4.64/p=0.969) Neurologicdisease 0.81(0.16–3.92/p=0.760) Renaldisease 1.02(0.22–4.64/p=0.969) Cardiovasculardisease 2.53(1.23–5.26/p=0.006) SolidOrganTumor 3.23(0.55–33.48/p=0.138) Previoushospitalization 1.19(0.60–2.35/p=0.597) SequentialOrganAssessmentFailure
(SOFA)score
0–6 (Referencegroup)
7–9 1.96(0.58–6.61/p=0.276)
10–12 0.71(0.17–3.03/p=0.648)
13–14 1.25(0.07–22.13/p=0.879)
GlasgowComaScale(GCS)score
Mild (Referencegroup)
Moderate 0.95(0.30–3.03/p=0.931)
Severe 1.40(0.64–3.08/p=0.397)
Invasivedevices
Endotrachealtube 2.75(0.94–9.09/p=0.041) Centralvenouscatheter 2.92(1.07–8.74/p=0.020) Foleycatheter 1.62(0.61–4.52/p=0.289) Infectiontype
Bloodstreaminfection 0.56(0.29–1.08/p=0.064) Vent.-assoc.pneumonia 6.43(1.99–26.90/p=0.000) Urinarytract 1.88(0.64–5.96/p=0.203) Skinandsofttissue 1.38(0.23–9.73/p=0.676) Meningitis 2.1(0.11–125.33/p=0.539) Intraabdominal 0.45(0.20–1.00/p=0.034) Timeb/wcultureandinitiationof
meropenemtreatment
Immediate (Referencegroup)
<24hours 0.78(0.31–1.96/p=0.597) 24–72hours 1.13(0.43–3.02/p=0.800)
72+hours 0.96(0.33–2.83/p=0.941)
ObtainedpriortoICU 0.88(0.40–1.96/p=0.760) Multidrugresistantbacteria 1.28(0.57–2.91/p=0.516) Useofgenericmeropenem 2.32(1.18–4.59/p=0.008) Infectiousorganism
P.aeruginosa 1.57(0.61–4.20/p=0.303) Enterobacteria 0.64(0.24–1.63/p=0.303)
effectivenessand safety due to severity of illness. Critical patientsusuallyhavealterationsinthevolumeofdistribution, tissueperfusion and renal functions among others,which mayleadtosignificantchallengesinachievingrecommended pharmacokineticandpharmacodynamicparametersfor opti-mal treatment against bacterial infections.28 Second, only patientswithdocumentedGram-negativeinfections suscepti-bletomeropenemwereincludedtomaximizethelikelihoodof successfultreatmentwiththeselectedantibiotics.Toreduce confoundingfactorsinthemortalityanalysis,patientswith invasivefungalinfectionswereexcluded.Third,theeconomic analysis allowedthe comparison ofcost ofhospitalization
Table3–Multivariateanalysis.
Variable OddsRatio(95%CI/p-value)
Sequentialorganfailureassessment score (Group1) 1.07(0.15–7.50/p=0.943) (Group2) 0.73(0.08–6.62/p=0.776) (Group3) 0.64(0.02–25.33/p=0.812) Glasgowscore (Group1) 2.76(0.20–37.98/p=0.449) (Group2) 31.33(0.60–1639.36/p=0.088) Treatmentwithgenericmeropenem 18.45(1.45–232.32/p=0.024) Comorbidities Diabetes 2.93(0.40–21.38/p=0.288) Cardiovasculardisease 18.18(1.25–262.63/p=0.033) Infectiontype Bloodstream 3.40(0.27–41.61/p=0.338) Vent.-assoc.pneumonia 5.92(0.16–208.88/p=0.328) Urinarytract 2.49(0.07–82.87/p=0.609) Intraabdominal 4.54(0.25–79.87/p=0.301) Timeb/wcultureandinitiationof
meropenemtreatment
(Group1) 0.64(0.06–6.81/p=0.717)
(Group2) 0.27(0.02–2.97/p=0.288)
(Group3) 0.05(0.00–4.09/p=0.189)
(Group4) 1.15(0.09–14.71/p=0.910)
Solidorgantumor 3.11(0.08–107.83/p=0.530)
aswellasthecalculationofincrementalcostofsurvivalfor each treatmentused.Fourth,thegroupsofpatientstreated withgenericandbrand-namemeropenemwerecomparable intermsofageandseverityofinfections.Furthermore,the groupofpatientstreatedwiththebrand-namemoleculehad ahigherprevalenceofcardiovasculardisease,whichwasa significantriskfactorformortality.
Pharmacoeconomicanalysesareimportantforan evalu-ation ofcosts and benefits ofhealth interventions. In the present study, a cost-effectiveness model was created to comparecostswhenusingeachmolecule.Thenet healthcare-associated costs were included in the assessment ofeach molecule, as well as the secondary costs ofcomplications resultingfromtherapeuticfailureandadversereactions asso-ciatedwiththeantibiotic.Ontheotherhand,thecost-of-stay in the ICU was higher in the generic group due to the developmentofmorecomplicationsandunfavorableclinical progression.Attheend,therewerenosignificantdifferences inthecostsoftreatmentforeachepisodeofinfectionbetween cohorts,whichisthemostcogentargumentforusinggenerics. Whentheincrementalcosteffectivenessratio(ICER)was calculatedforthebrand-nameandgenericmoleculesinour study,theICERanalysisshowedthattreatmentwith brand-namemeropenemconfersgreaterpatientsurvivalatalower cost and is therefore isa bettertreatment option than its genericcounterpart.
Alimitationofthisstudy isthatonly67%ofthe antici-patedsamplesizeof252wasachieved.Thisoccurredprimarily duetotheinclusionandclinicalfollow-upcriteria,whichwas strictandthereforeledtotheexclusionofmanypatients.Also, secondarytothesmallersamplesizeachieved,somevariables like SOFAor other non-cardiovascularcomorbiditieswhere notfoundtobeassociatedwithmortalityinthe multivari-ateanalysis.Whileasmallersamplemayaltertheprecision
ofthestudy,ourresultsdemonstrateastrongstatistical asso-ciationthatisunlikelytobebychance.EventhoughtheGA hadahigherincidenceofventilatorassociatedpneumoniae whichmaycontributeinparttothehighermortality,the mul-tivariateanalysisdidnotshowanydifferenceassociatedwith thistypeofinfection.Also,asweexplainedbefore,wedidnot findanyotherfactorsthatcouldexplainthehighermortality withGAlikechangesintheantibioticprescriptionorinfection controlpractices.
In conclusion, the use of brand-name meropenem for thetreatmentofGram-negativeinfectionssusceptibleto car-bapenems inthe ICU is amore cost-effective option than genericmeropenem.Institutions shouldfollow clinicaland microbiologicoutcomesofpatientstreatedwithantibiotics, whichinturnmayallowforearlydetectionoftherapeutic fail-ure.Ultimately,thisapproachcanprovidedatathatwillhelp drugproducersimprovethedevelopmentofantibiotics.
Financial
support
ThisstudywasfundedbytheInternationalCenterfor Medi-calTrainingandResearch(CIDEIMinSpanish).Thisstudydid notreceiveanyfundingfromdrugmanufacturersoranyother sources.
Conflicts
of
interest
Theauthorsdeclarenoconflictsofinterest.
Thanks
WearegratefulfortheassistancewereceivedfromObedDavid SuárezAnaya,CarmenElisaLlanosUribe,LuzStellaSalazar, andCamilaMarinPeralta.
Author
information
KarenOrdó ˜nezdesignedthestudy,collectedandinterpreted data,revisedthemanuscript,andapprovesofthefinalversion. Conceptualization,Datacuration,Investigation,Methodology, Supervision,Validation,Visualization,Writingoriginaldraft, writingreviewandediting.Address:Carrera18#12-75Torre1 Consultorio1205,PostalCode660003,Pereira,Colombia.
MaxM.Feinsteincollectedand interpreteddata,drafted themanuscript,andapprovesofthefinalversion.Address: 2058E.115thSt.,Cleveland,Ohio,PostalCode44106,USA.Data curation,formalanalysis,writingoriginaldraft,writingreview andediting.
Sergio Reyes collected and interpreted data,revised the manuscript,andapprovesofthefinalversion.Datacuration, formalanalysis, investigation,supervision,validation, writ-ingoriginaldraft.Address:Av.LaMaria#19-225,PostalCode 760031,Cali,ValledelCauca,Colombia.
Cristhian Hernández-Gómez designed the study, inter-pretedthedata,revisedthemanuscript,andapprovesofthe finalversion.Conceptualization,Formal analysis, investiga-tion,methodology,software,supervision,validation,writing original draft, project administration writing review and
editing.Address:Cra9#131A-02,LabdeInvestigacion2Piso, PostalCode110121,Bogotá,Colombia.
ChristianPallaresdesignedthestudy,interpretedthedata, revised the manuscript,and approves ofthe final version. Conceptualization, formal analysis, methodology, software, validation,writingoriginaldraft,projectadministration, writ-ingreviewandediting.Address:Av.LaMaria#19-225,Postal Code760031,Cali,ValledelCauca,Colombia.
María V. Villegas designed the study, revised the manuscript,andapprovesofthefinalversion. Conceptualiza-tion,funding acquisition,projectadministration, resources, supervision, validation, visualization, writing-review and editing.Address:Cra9#131A-02,LabdeInvestigacion2Piso, PostalCode110121,Bogotá,Colombia.
Allauthorsagreetobeaccountableforallaspectsofthe workandensuretheaccuracyandintegrityofthestudy.
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