Early switch/early discharge opportunities for hospitalized patients with methicillin-resistant Staphylococcus aureus complicated skin and soft tissue infections in Brazil

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w w w . e l s e v ie r . c o m / l o c a t e / b j i d

The

Brazilian

Journal

of

INFECTIOUS

DISEASES

Original

article

Early

switch/early

discharge

opportunities

for

hospitalized

patients

with

methicillin-resistant

Staphylococcus

aureus

complicated

skin

and

soft

tissue

infections

in

Brazil

Guilherme

H. Furtado

a

_,

_Jaime

_Rocha

b

_,

_Ricardo

_Hayden

c

_,

_Caitlyn

_Solem

d

_,

Cynthia

Macahilig

e

_,

_Wing

_Yu

_Tang

f

_,

_Richard

_Chambers

g

_,

Maria

Lavínea

Novis

de

Figueiredo

h

_,

_Courtney

_Johnson

d

_,

_Jennifer

_Stephens

d,∗

_,

Seema

Haider

i

a_Universidade_Federal_de_São_Paulo,_Comissão_de_{Epidemiologia}_Hospitalar,_São_Paulo,_SP,_Brazil b_Clínica_Médica_e_{Infectologia,}_Pontifícia_Universidade_Católica_do_Paraná_(PUC-PR),_Curitiba,_PR,_Brazil c_Hospital_Guilherme_Alvaro,_São_Paulo,_SP,_Brazil

d_Pharmerit_{International,}_Bethesda,_MD,_USA e_Medical_Data_Analytics,_Parsippany,_NJ,_USA f_Pﬁzer_Inc,_New_York,_NY,_USA

g_Pfizer_Inc,_{Collegeville,}_PA,_USA h_Pfizer_Inc,_São_Paulo,_SP,_Brazil i_Pfizer_Inc,_Groton,_CT,_USA

a

r

t

i

c

l

e

i

n

f

o

Articlehistory:

Received21November2018 Accepted6April2019 Availableonline9May2019

Keywords: IV-to-POswitch Lengthofstay Clinicalcriteria Antibiotictherapy Economics

a

b

s

t

r

a

c

t

Background:Earlyantibioticswitchandearlydischargeprotocolshavenotbeenwidely stud-iedinLatinAmerica.Ourobjectivewastodescribereal-worldtreatmentpatterns,resource use,andestimateopportunitiesforearlyswitchfromintravenoustooralantibioticsand earlydischargeforpatientshospitalized withmethicillin-resistantStaphylococcus aureus

complicatedskinandsoft-tissueinfections.

Materials/methods:Thisretrospectivemedical chartreviewrecruited72 physiciansfrom Braziltocollect datafrom patientshospitalized withdocumented methicillin-resistant

StaphylococcusaureuscomplicatedskinandsofttissueinfectionsbetweenMay2013and May2015,anddischargedalivebyJune2015.Datacollectedincludedclinicalcharacteristics andoutcomes,hospitallengthofstay,methicillin-resistantStaphylococcusaureus-targeted

intravenousandoralantibioticuse,andearlyswitchandearlydischargeeligibilityusing literature-basedandexpert-validatedcriteria.

Results:A total of 199 patient charts were reviewed, of which 196 (98.5%) were pre-scribedmethicillin-resistantStaphylococcusaureus-activetherapy.Onlyfourpatientswere switched from intravenousto oral antibiotics while hospitalized.The mean length of

∗ _{Corresponding}_author.

E-mailaddress:jstephens@pharmerit.com(J.Stephens). https://doi.org/10.1016/j.bjid.2019.04.003

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methicillin-resistantStaphylococcusaureus-activetreatmentwas14.7(standarddeviation, 10.1)days,with14.6(standarddeviation,10.1)totaldaysofintravenoustherapy.Themean lengthofhospitalstaywas22.2(standarddeviation,23.0)days.Themostfrequentinitial methicillin-resistantStaphylococcusaureus-activetherapieswereintravenousvancomycin (58.2%),intravenousclindamycin(19.9%),andintravenousdaptomycin(6.6%).Thirty-one patients (15.6%)weredischargedwithmethicillin-resistant Staphylococcusaureus -active antibioticsofwhich80.6%receivedoralantibiotics.Sixty-twopatients(31.2%)metearly switchcriteriaandpotentiallycouldhavediscontinuedintravenoustherapy6.8(standard deviation,7.8)dayssooner,and65patients(32.7%)metearlydischargecriteriaand poten-tiallycouldhavebeendischarged5.3(standarddeviation,7.0)dayssooner.

Conclusions: Only2%ofpatientswereswitchedfromintravenoustooralantibioticsinour studywhilealmostone-thirdwereearlyswitcheligible.Additionally,one-thirdof hospi-talizedpatientswithmethicillin-resistantStaphylococcusaureuscomplicatedskinandsoft tissueinfectionswereearlydischargeeligibleindicatingopportunityforreducing intra-venoustherapyanddaysofhospitalstay.Theseresultsprovideinsightintopossiblebeneﬁts ofimplementationofearlyswitch/earlydischargeprotocolsinBrazil.

Introduction

Methicillin-resistant Staphylococcus aureus (MRSA) compli-catedskinandsofttissueinfections(cSSTIs),whichinclude allskinandsofttissueinfectionsbeyondthesuperﬁcialand uncomplicated rangingfrom cellulitis tonecrosis, pose an enormousclinical and economic burdenwithinthe Brazil-ianhealthcaresystem.1–3 _The_prevalence_of_MRSA_infection isincreasing inLatinAmerica reaching 40–50%in mostof LatinAmericancountries.4,5_In_Brazil,_45–64%_of_S._aureus cul-tureshavebeenreportedtobemethicillin-resistant.4,5_MRSA ishighlyendemicinBrazilian hospitalswith6.1%ofadult patientsand2.3%ofpediatricpatientsadmittedtoatertiary carehospitalscreeningpositiveforMRSA.6

Intravenous(IV)antibiotictherapyisthemostfrequently used treatment among patients hospitalized with cSSTIs, thoughoutpatientparenteralantibiotictherapies(OPAT)and oral (PO) antibiotic therapies exist. Clindamycin, linezolid, doxycycline,trimethoprim/sulfamethoxazole(TMP/SMX),and rifampicinaloneorincombinationwithanotheragent,may be used to treat MRSA cSSTIs; though careful selection is necessaryinpatientswithconsiderationtowardlocalMRSA resistance.7,8 _Treatment_with_outpatient_and_oral_antibiotics allowforearlierdischarge,reducedirectandindirectmedical costs,andhavesimilarcureratestothoseofIVantibiotics.9 OncecSSTIsare stabilized,morbidityandmortalityremain lowregardlessofantibioticformulationallowingforaswitch fromin-hospitalIVtreatmenttoOPATorPOtherapies.

Though there has been an increase in MRSA surveil-lance and data collection in Brazil and Latin America, real-world data speciﬁc to MRSA treatment in Latin America is still limited. A previously published real-world chart review of MRSA cSSTI carried out in 12 European countries evaluated treatment patterns, clin-ical outcomes, and economic outcomes of patients switched from IV to PO therapy or discharged on OPAT.10,11 _Our _study _sought _to _apply _this _approach _to

evaluateearlyswitch(ES)andearlydischarge(ED) opportuni-tiesinMRSAcSSTIpatientsinBrazil.

Methods

This retrospective observational medical chart review recruited72physicians(34infectiousdiseasespecialists, 38 internalmedicine specialists)from 79 hospitalsand health clinicsinBrazil,whocollecteddataon199patients.Thisstudy wasanextensionofachartreviewin12Europeancountries thathasbeenpublishedelsewhere.10,11 _Data_were_collected from medicalrecordsofpatientstreatedforadocumented MRSAcSSTI,andadmittedtothehospitalbetween01May 2013and30May2015,anddischargedaliveby30June2015. Patientswererandomlysampledfordataonreal-world treat-ment patterns, clinical outcomes, and resource utilization. Thosewho could havebeenswitchedfrom IVtoPOMRSA therapy andthose who could havebeen dischargedearlier (via useoforalantibioticsor OPAT)based ontheeligibility criteriainTable1wereidentiﬁed,andthepotentialreductions in IV-line usage for antibiotic administration and hospital lengthofstay(LOS)werecalculated.

Patientselection

Studyinvestigators(hospital-basedinfectiousdisease special-ists,internalmedicinespecialistswithaninfectiousdisease sub-specialty,ormedicalmicrobiologists)identiﬁedsubjects eligible for inclusion. To be included, patients must have hadamicrobiologicallyconﬁrmedMRSAcSSTI(e.g.,deepor extensive cellulitis,infectedwoundor ulcer,majorabscess or other soft tissue infection requiring substantial surgical intervention),andreceived≥3daysofIVanti-MRSA antibi-oticsincluding,butnotlimitedto:clindamycin,daptomycin, fusidic acid, linezolid, rifampicin, teicoplanin, tigecycline, TMP/SMX,orvancomycin,duringtheirhospitalstay.Patients were excludediftheyhad beentreatedforthesame cSSTI

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Table1–IVandLengthofStayRelatedEndpoints

IV-relatedendpoints •ActuallengthofIVusage:timebetweeninitiationofMRSA-activeIVtherapyandlastdayofMRSA-activeIV therapy(forpatientsswitchedfromIVtoPO)ordischarge(IVonlypatients)

•ESeligibility:Atminimum,thefollowingkeycriterianeededtobemetpriortoactualIVdiscontinuation: Stableclinicalinfection

Afebrile/temperature<38◦Cfor24h

WBCcountnormalizing,WBCnot<4×109_/L_or_>12_×₁₀9_/L

Nounexplainedtachycardia Systolicbloodpressure≥100mmHg

PatienttoleratesPOﬂuids/dietandabletotakePOmedicationswithnogastrointestinalabsorptionproblems •HypotheticalIVdays:DaysbetweenthedayofinitialMRSA-activeIVantibioticadministrationanddatewhen patientsatisﬁedthelastofthekeyEScriterialistedabove

•PotentialreductioninIVdays:DifferenceindaysbetweenactualandhypotheticalIVdaysamongESeligible patients

LOS-related endpoints

•LOS(frombeginningofcSSTIepisode):NumberofdaysfromcSSTIindexa_to_hospital_discharge

•EDeligibility:Atminimum,thefollowingcriterianeededtobemetpriortodischarge

AllkeyESeligibilitycriterialistedabove

Nootherreasontostayinhospitalexceptinfectionmanagement

•HypotheticalLOS:NumberofdaysfromcSSTIindexa_to_the_date_that_patient_satisﬁed_all_key_required_criteria

andactualLOS

•PotentialreductioninLOS(beddayssaved):DifferenceindaysbetweenactualandhypotheticalLOSamongED

eligiblepatients

Abbreviations:cSSTI,complicatedskinandsofttissueinfection;ED,earlydischarge;ES,earlyswitch;IV,intravenous;LOS,lengthofstay;MRSA,

methicillin-resistantStaphylococcusaureus;OPAT,outpatientparenteralantibiotictherapy;PO,oral;WBC,whitebloodcell.

a _Date_of_admission_for_patients_admitted_for_cSSTI;_cSSTI_diagnosis_date_otherwise._In_cases_where_the_cSSTI_diagnosis_date_was_before

admission,thedateofadmissionwasused.

within three months of hospitalization, or had suspected or proven diabetic foot infections, osteomyelitis, infective endocarditis, meningitis, joint infections, necrotizing soft tissueinfections,gangrene,prostheticjointinfection,or pros-thetic implant/device. Additionally, patients were excluded if they were less than 18 years old, pregnant or lactat-ing, had signiﬁcant concomitant infection at other sites, wereimmunosuppressed(e.g.,diagnosedhematologic malig-nancy,neutropenia,orrheumatoidarthritis;receivingchronic steroids or cancer chemotherapy), or enrolled in another cSSTI-relatedclinicaltrial.

Keyoutcomes

The key study outcomes were patient treatment patterns, clinicaloutcomes,andopportunitiesforearlyswitchorearly discharge.

TreatmentpatternsanalyzedincludedtimetoMRSA-active treatmentfromcSSTIindexdateandnumberofMRSA-active treatmentreceived.Patients’ﬁrst,last,anddischarge(if appli-cable) MRSA-active treatment were recorded. Additionally, length of total antibiotic therapy, (time between initiation ofMRSA-active therapy and last day ofMRSA-active ther-apyordischarge); lengthofIVantibiotictherapy(subsetof MRSA-activetherapydaysforwhichIVantibioticswere pre-scribed)wereassessed.Lengthofstay(numberofdaysfrom hospitaladmissionforpatientsadmittedforcSSTI,orcSSTI diagnosisdatetohospitaldischarge)wasalsocalculatedforall patients.

Clinicaloutcomesincludedclinicalresponseatendofeach MRSA-activetherapy,endoffullMRSA-activetreatment,and athospitaldischarge.DevelopmentofIV-lineinfections,super infections,andseveresepsisweredocumented.Patientswere alsofollowedtorecordcSSTIrelapseduetoMRSAwithin30

daysofdischargeorunplannedre-hospitalizationforcSSTIor otherhealthissues.

Literaturereviewandexpertconsensuswereusedtocreate ESandEDeligibilitycriteriaapplicabletoreal-worldclinical settings.12–18_For_ES_eligibility,_at_a_minimum,_patients_had_to meetallofthefollowingkeycriteriapriortoIVantibiotic dis-continuation: stable clinical infection, afebrile/temperature <38◦C for 24h, normalized white blood cell (WBC) count (4×109_/L_<_WBC_<₁₂_×₁₀9_/L), _no _unexplained _tachycardia, systolic blood pressure ≥100mmHgableto toleratePO flu-ids/diet and take PO medication with no gastrointestinal absorptionproblems.ForEDeligibility,ataminimum,patients hadtomeettheabovekeycriteriaforESpriortodischargeand havenootherreasontoremaininthehospitalexceptfor infec-tionmanagement.Toestimateresourceusesavings,potential reductioninIVdayswascalculatedforESpatientsandbed dayssavedwerecalculatedforEDpatients,usinghypothetical andactualtreatmentpatterns.HypotheticallengthofIV ther-apywascalculatedasthelengthoftimebetweendateofinitial MRSA-activeIVtherapyanddatewhenpatientsatisfiedkey EScriteria.PotentialreductioninIVdayswasthedifference indaysbetweenactuallengthofMRSAtargetedtherapyfrom hypotheticallengthofMRSAtargetedtherapy. Hypothetical LOSwascalculatedasnumberofdaysfromcSSTIindexdate todatethatpatientssatisfiedallkeycriteria.Beddayssaved wasthedifferenceindaysbetweenactualandhypothetical lengthofstayforEDeligiblepatients.Theeconomicimpactof meancostperbeddayssavedinEDeligiblepatientswas cal-culatedbymultiplyingthebeddayssavedbyaBrazil-specific unitcostof$31internationaldollars(Intl.)(45Brazilianreal [BRL])perbeddaybasedonWorldHealthOrganization (WHO)-reportedunitcostsforprovidingaBrazilhospitalbeddayin theyear2007;thiswasreportedininternationaldollars(local currencyunits)andadjustedforinflation(percentchangein

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Table2–PatientandDiseaseCharacteristics

Variable Brazil(n=199)

Age,mean(SD) 52.0(5.7)

Male,n(%) 128(64.3)

Caucasian,n(%) 92(46.2)

Atleastonecomorbidity,N(%) 155(77.9)

Diabetes 76(49.0)

Coronaryarterydisease(incl.myocardialinfarction,coronaryarterybypassgraft,etc.) 43(27.7) Peripheralvasculardisease 29(18.7)

Chronicpulmonarydisease 23(14.8)

Congestiveheartfailure 21(13.5)

OtherComorbidity 17(11.0)

Diabeteswithendorgandamage 15(9.7)

Mildliverdisease 12(7.7)

PrimaryreasonforhospitalizationistreatmentofMRSAcSSTI,n(%) 153(80.1)

TypeofcSSTI,n(%)

Deep/extensivecellulitis 57(28.6)

Infectedburn 9(4.5)

Infectedulcer 35(17.6)

Majorabscess 26(13.1)

Posttraumaticwoundinfection 17(8.5)

Surgicalsiteinfection 55(27.6)

SourceofcSSTI,n(%)

Communityacquired 117(58.8)

Healthcare-associated(priorhospitalizationinthepast90days,residenceinanursinghomeorextendedcarefacility 32(16.1) Hospitalacquired(>48hafteradmission) 35(17.6)

Unknown/notdocumented 15(7.5)

MRSAinfectionwithin12monthspriortohospitalization,n(%) 11(5.5%)

SurgicalprocedurerelatedtocSSTItreatment,n(%) 52(26.1)

Incision/drainage 28(53.8) Debridement 21(40.4) Othera ₂_(3.8) Revascularization 2(3.8) Closureofwound 1(1.9) Removalofprosthesis 1(1.9)

Infectionsduringhospitalization,n(%)

IV-lineinfection 5(2.5)

Superinfection 10(5.0)

Severesepsisorsepticshock 51(25.6)

Abbreviations:cSSTI,complicatedskinandsofttissueinfection;h,hour;incl,include;IV,intravenous;MRSA,methicillin-resistant

Staphylo-coccusaureus;SD,standarddeviation.

a _Other₌_skin_grafting,_resection.

consumerpriceindex)totheyear2015.19,20_Costs_included_by theWHOrepresentthe“hotel”componentofhospitalcosts, suchaspersonnel,capital,andfood,anddonotincludedrug anddiagnostictestcosts.

Statisticalanalysis

Descriptiveanalyses were conductedforall outcomes; fre-quencies and percentages for categorical variables, and means,medians,andinterquartilerangesforcontinuous vari-ables.ResultswereanalyzedusingSASsoftwareversion9.4.

Results

Patientandhospitalcharacteristics

Data was collected from medical chartsof 199patients in BrazilwithMRSAcSSTIs.Almosthalfofpatientswere Cau-casian(45%),followedbyequalproportionsofblack/African and Latino patients(19%, respectively). Mostpatientswere male (64%),andtheaverageage athospitaladmissionwas 52years(Table2).Morethanthree-quartersofpatients(78%)

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Table3–ActualAntibioticUseinPatientsTreatedwithMRSA-ActiveAntibiotics

Variable Brazil(n=196)

PatientswitchedfromIVtooralinpatientMRSA-activeantibiotictreatment,n(%) 4(2.0)

DaystoMRSAtargetedtherapy,fromcSSTIindexdate,n(%)

OnorbeforecSSTIindex 124(63.3)

1–2dayspostcSSTIindex 29(14.8)

3+dayspostcSSTIindex 43(21.9)

NumberofMRSAtargetedcoursesoftherapy,n(%)

1 161(82.1)

2 33(16.8)

3 2(1.0)

MRSAactivedaysoftherapy(includingPO),mean(SD) 14.7(10.1) MRSAactiveIVdays,mean(SD) 14.6(10.1)

MRSAtargetedantibioticsusedininitialline,n(%)

VancomycinIV 114(58.2) ClindamycinIV 39(19.9) DaptomycinIV 13(6.6) TMP-SMXIV 7(3.6) LinezolidIV 6(3.1) Othera ₁₇_(8.6)

MRSAtargetedantibioticsusedinlastline,n(%)

VancomycinIV 104(53.1) ClindamycinIV 28(14.3) DaptomycinIV 22(11.2) LinezolidIV 18(9.2) TMP-SMXIV 6(3.1) Otherb ₁₈_(9.1)

Patientreceivedtargetedantibioticatdischarge,n(%) 31(15.8)

Oraltargetedtherapy 25(80.6)

MRSA-activeantibioticsprescribedatdischarge,n(%) 31(15.8)

ClindamycinPO 13(41.9) LinezolidPO 5(16.1) TMP-SMXPO 3(9.7) DaptomycinIV 3(9.7) VancomycinIV 2(6.5) CiproﬂoxacinPO 2(6.5)

Abbreviations:cSSTI,complicatedskinandsofttissueinfection;IV,intravenous;MRSA,methicillin-resistantStaphylococcusaureus;PO,oral;

SD,standarddeviation;TMP-SMX,trimethoprim/sulfamethoxazole.

a _Other_includes:_cefuroxime_IV,_{ciproﬂoxacin}_IV₊_clindamycin_IV,_clindamycin_IV,_clindamycin_IV₊_linezolid_IV,_clindamycin_IV₊_TMP-SMX_IV,

clindamycinPO,daptomycinIV,doxycyclinePO,linezolidIV,oxacillinIV,TMP-SMXIV,teicoplaninIV,teicoplaninIV+tigecyclineIV,tigecycline

IV,trimethoprimIV.

b _Other_includes:_{ciproﬂoxacin}_IV,_linezolid_PO,_oxacillin_IV,_{piperacillin/tazobactam}_IV,_TMP-SMX_PO,_teicoplanin_IM,_teicoplanin_IV,_tigecycline

IV.

reportedcomorbidities,withdiabetes(49%),coronaryartery disease(28%)andperipheralvasculardisease(19%)beingmost frequentlyreported.About80%ofpatientsreportedtreatment ofMRSAcSSTIastheprimaryreasonforhospitalization,with 29%ofpatientspresentingwithdeeporextensivecellulitis, 28%withasurgicalsiteinfection,and18%withaninfected ulcer.Overhalf(59%)ofallcSSTIswerecommunityacquired, and a smaller proportion were hospital acquired (18%) or healthcare-associated(16%) infections.Only6%ofpatients hadbeeninfectedwithMRSAayearpriortohospitalization.

Allbutoneofthe79hospitalsiteshadanantibiotic sub-committeeorsteeringcommittee.FewerhospitalshadanIVto POantibioticswitchprotocol(20%)ordischargeprotocol(11%) forpatientsadmittedforcSSTIMRSA.However,one-fourthof hospitalsreportedhavingOPATavailable.

Actualtreatmentpatternsandhealthcareresource utilization

Allbutthreepatients(99%)receivedatleastoneMRSA-active therapy. Ofpatients treated withMRSA-active therapy, 161 patients(82%)didnotrequiresubsequentantibiotictherapy, 33patients(17%)requiredtwocourses,andtwopatients(1%) requiredthreecourses(Table3).Themeantimeof adminis-trationofMRSA-activetherapywas2.1days(SD6.3)following MRSAcSSTIdiagnosis.Onlyfourpatients(2%)wereswitched fromIV-to-POMRSA-activetherapywhilehospitalized. Aver-age LOS from cSSTI diagnosis through discharge was 20.7 (SD18.6)days.Aboutone-quarterofcSSTIs(26%)warranted surgical procedures, incision and drainage ofthe infection (54%)anddebridement(40%)wereperformedmostfrequently.

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Table4–MRSAcSSTISusceptibilityProﬁle Antibiotica _All Ntested %sensitive Linezolid 116 100 Vancomycin 135 97.0 Tigecycline 87 96.6 Daptomycin 62 91.9 Quinupristin–dalfopristin 18 66.7 Rifampicin 48 64.6 Trimethoprim/Sulfamethoxazole(TMP-SMX) 119 37.0 Clindamycin 122 36.1 Minocycline 22 27.3 Doxycycline 63 20.6 FusidicAcid 28 17.9 Ciproﬂoxacin 121 11.6 Trimethoprim 44 6.8 B-lactamantibiotic/penicillin 102 5.9

a _Other_antibiotics_with_<10_tests,_N_tested_(%_sensitive):_amikacin,₂_(100%);_polymyxin,₁_(100%);_gentamicin,₆_(66.7%);_oxacillin,₂_(50%).

Table5–MRSAClinicalOutcomes

Variable All(n=196)

Clinicalresponseatdischarge,n(%)

Curea ₁₀₇_(54.6)

Improvementb ₆₉_(35.2)

Failure 14(7.1)

Indeterminatec ₆_(3.1)

Outcomes30dayspost-discharge(n=199)

cSSTIrelapseduetoMRSA,n(%) 2(1.0)

Daysfromdischargetorelapse,mean(SD) 17.0(12.7)

Re-hospitalizationforcSSTIduetoMRSA,n(%) 2(1.0)

LOS,mean(SD) 19.5(6.4)

Re-hospitalizationforanyreason,n(%) 11(5.5)

Abbreviations:cSSTI,complicatedskinandsoft-tissueinfection;LOS,lengthofstay;MRSA,methicillin-resistantStaphylococcusaureus;SD,

standarddeviation.

a _Cure:_resolution_of_All_signs_and_symptoms_of_cSSTI_due_to_{MRSA/improvement}_to_such_an_extent_that_further_{antimicrobial}_therapy_was_not

necessary.

b _Improvement:_improvement_in_signs_and_symptoms_of_cSSTI_due_to_MRSA.

c _{Indeterminate:}_inability_to_determine_an_outcome.

Severesepsisorsepticshockoccurredamongapproximately one-quarter(26%)ofthosehospitalized,whilesuperinfection (5%)andIV-lineinfection(3%)wererarelyfound.

Themostfrequentlyprescribedantibioticsdidnotchange betweeninitiallineandfinallinetreatment,withvancomycin IV(initial58%,final 53%), clindamycinIV(initial20%,final 14%), and daptomycin IV (initial 7%, final 9%) used most frequently.However,analysisoffinalinpatientMRSA-active antibiotic regimens showed that throughout the course of treatment,theproportionofinpatientsreceivingvancomycin IV or clindamycin IV decreased, while the proportion of patientsreceivingdaptomycinIVorlinezolidIVincreased.At discharge,31 patients(16%)wereprescribed aMRSA-active antibiotic, and four-fifths ofthese were oraltargeted ther-apy.ClindamycinPO(42%),linezolidPO(16%),andTMP-SMX

PO(10%)werethemostcommonlyprescribedoralantibiotics atdischargewhiledaptomycinIV(10%)andvancomycinIV (7%)werethemostcommonIVantibiotics.Antibiotic suscep-tibilitiesin thissample arepresentedin Table4and show susceptibilityrates<40%forthecommonlyusedoralagents TMP-SMX and clindamycin. Mean length of MRSA-active antibiotictreatmentregardlessofroute(i.e.,IV,intramuscular, orPO)was14.7(SD10.1)days,whileMRSA-activeIVantibiotic treatmentlastedameanof14.6(SD10.1)days.

Atdischarge,overhalfofpatients(55%)showedresolution ofsigns and symptomsor improvementtosuchanextent thatfurthertherapywasnotnecessary(Table5).Intotal,69 patients(35%)weredischargedwithanimprovementintheir signsandsymptoms,and14(7%)weredischargedafter fail-ure tocureor improvecSSTIsigns andsymptoms. Relapse

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Potential to save 6.8 IV days on average due to ES eligibility Potential to save 5.3 bed days on average due to ED eligibility ES eligible 31.2% ED eligible 32.7% 25.0 20.0 15.0 10.0 5.0 0.0 Da ys

IV line days in ES eligible patients (n = 62)

Bed days in ED eligible patients (n = 65) Actual 15.5 Actual 22.2 Hypothetical 8.7 Hypothetical 16.9

Fig.1–BrazilComparisonofActualandHypothetical IV-lineandBedDaysinES-andED-eligiblePatients. Abbreviations:ED,earlydischarge;ES,earlyswitch;IV, intravenous.

andre-hospitalizationforacSSTIduetoMRSAwithin30days post-dischargeoccurred inonlytwo(1%)patientswhile re-hospitalizationforanyreasonoccurredin11(6%)patients.

ActualandhypotheticaloutcomesbasedonES/ED eligibility

Atotalof62(31%)patientsmetall sixkeyEScriteriaprior toactualIVdiscontinuation.AmongtheES-eligiblepatients, theactualmeanlengthofIVtherapywas15.5(SD11.1)days but hypotheticallycould have been 8.7(SD8.9) dayswhen removingdaysafterpatientsmetallEScriteria,suggestinga potentialreductioninIVtherapydurationof6.8(SD7.8)days (Fig.1).

Approximatelyone-third(32.7%)ofpatientsmetallkeyED criteriapriortohospitaldischarge.TheactualmeanLOSfor patientsmeetingkeyEDcriteriawas22.2(SD23.0)days;the hypotheticalLOSforthesepatientswas16.9(SD21.5)days, suggestingapotentialreductioninLOSof5.3(SD7.0)days. Assuminganaveragecostof$31Intl,(45real)perbedday, thetotalsavingswouldbe$164Intl.(239real)inbed-daycost savingsperED-eligiblepatient.

Discussion

Nootherstudieshaveusedpatienttreatmentdatatoevaluate real-worldclinicalpracticeandopportunitiesforESandEDin hospitalizedpatientswithMRSAcSSTIsinBrazil.Wefound that,priortoactualdischarge,almost one-thirdofpatients withMRSAcSSTIsmetcriteriaforESandED.Forthosefound eligible, LOS could have been reduced by 5.3 days and IV therapydaysby6.8days.Theseresultsofferinsightintothe potentialpolicyandeconomicimplicationsofidentifyingES and EDeligible patients. Ourstudy provides asnapshot of managementpatternsinBrazil,speciﬁcallyclinicaloutcomes andresourceutilizationdetails,makingthisdatasetunique.

OurresearchdemonstratesagreatopportunityforES/ED antibioticpoliciesinBrazilwhencomparedwithEuropeand

USAwhereearlydischargepoliciesalreadyexistinsome insti-tutions.Though31%ofpatientsonIVantibiotictherapieswere eligibleforESand33%ED,only2%wereswitchedfrom IV-to-POtherapies,andpotentialdecreasesinLOStotalled5.3days and6.8IVdays.TheratesofESandEDeligibilityobservedin ourstudyaresimilartoﬁndingsinpriorresearchthatshowed 30–50% of patients in Europe and United States could be switchedfromIVtoPOantibiotictherapy12,16,21–24_and_20–30% dischargedearlieronPOantibiotictherapy.12,16,23_Similar_rates ofESandEDeligibility,usinganidenticalmethodology,have beenreportedina12-countrystudyinEurope.Ratesof eligibil-ityrangedfrom12.0%(Slovakia)to56.3%(Greece)forES,and 10.0%(Slovakia)to48.2%(Portugal)forED,whichareinclusive ofBrazil’seligibilityratesof31%and33%,respectively.10,25

OurresultsshowtheimportanceoftakingMRSA suscep-tibility into accountwhendecidingupon patientregimens. VancomycinIVand,daptomycinIVwerefrequentlyprescribed asactivetreatmentsagainstMRSA,bothofwhichshow sus-ceptibilityabove 90%inthis sample(Table4).Clindamycin IV which presented susceptibility rates of 36% only when testedagainstMRSAsamples,wasthesecondmostcommonly used therapy inthe initialand ﬁnal inpatientactive treat-ment regimens. Inaddition, clindamycinPO wasthe most prescribed antibiotic atdischarge, representing 42% of dis-chargedpatientsregimens.Infact,thethreePOtherapiesmost frequentlyprescribedondischargerepresented68%ofall regi-menssuggestingotherPOantibiotictherapiesshouldbekept inmind.

Because Brazil does not have a national antimicrobial resistance surveillance system and previous MRSA studies sampled a small number of centers, our study provides additional information to the literature. The high rates of antibiotic resistance seen to TMP-SMX (63%), clindamycin (64%),anddoxycycline(80%)inourstudymaybeexplainedby auniqueepidemiologicsituationinBrazil.Thereisa hospital-acquired Brazilian endemic clone (BEC) of MRSA resistant tomanyantibiotics(<10%oftheseclonesaresusceptibleto clindamycin,sulfamethoxazole-trimethoprim,ciproﬂoxacin, gentamicin).26_A_more_resistant_strain_of_MRSA_in_Brazil under-scores the need for physiciansto be more cautious when actingonopportunitiesforESandED.Inourstudy,linezolid retainedhighactivityagainstMRSA(Table4)andcouldbe con-sideredanIVororaloptiongiventheresistancetoothermore frequentlyusedoralantibiotics.

Sincethisstudywasaretrospectivemedicalchartreview, ourresultsaresubjecttothewell-knownlimitationsofthis study design. Because informationwas limited to medical charts,datesthatpatientsmetcriteriaforESandEDwere esti-matedbasedondataavailableinthepatients’medicalrecords ifthesedateswerenotrecorded.Also,itwasnotpossibleto proactivelyapplyESandEDcriteriatodeterminetheactual (ratherthanpotential)cost-savingsusingaretrospectivestudy design.Ideally,theapplicabilityoftheESandEDcriteriaused inthisstudyneedstobevalidatedprospectively.Additionally, 99%ofthehospitalsinthisstudywereinurbansettings(vs. rural),wherepopulationdemographics,prevalenceof MRSA-cSSTI,accesstocare,andcostsmay differ.Also,treatment patterns presented inthis study representthe practicesof includedphysicianswhichmayvarybyphysiciansand hospi-talsduetomedicationaccess.Finally,onlypatientsdiagnosed

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withMRSAcSSTIbetween2013and2015wereincludedinthis studybutduetoincreasingMRSAresistanceanddecreasing drugsusceptibilitydiseasemanagementandtreatment pat-ternsmayhavechanged.

Conclusions

Thisisthefirstfullscalestudytoanalyzeearlyswitchand early discharge opportunitiesinLatin America,specifically inBrazil.Ourresultssuggestthatone-thirdofpatientswith MRSAcSSTIinBrazilcouldbeswitchedfromIVtooraltherapy anddischargedfromthehospitalearlierwhichcouldresult inpotentialcostsavingfortheBrazilianhealthcaresystem. AlthoughspecifictocSSTIs,theseresultssuggestthat hos-pitalsinLatinAmericacouldconsideradoptingearlyswitch andearlydischargeprotocolstotheirantibioticstewardship strategies,increasingproviderandpatientbenefits.

Author

contributions

GuilhermeFurtado,JaimeRocha,RicardoHayden,CaitlynT. Solem,WingYuTang,JenniferM. Stephens,Richard Cham-bers,SeemaHaider,andMariaLavíneaNovisdeFigueiredo contributed to the study design. Cynthia Macahilig was involved in data acquisition. Caitlyn T. Solem, Jennifer M. Stephens,andCourtneyJohnsonundertookdataanalysis.All authorscontributedtotheinterpretationofdata,draftingof thismanuscript,andapprovedtheﬁnalmanuscript.

Disclosure

ThisstudywassponsoredbyPfizerInc. GuilhermeFurtado, JaimeRocha,andRicardoHaydenwere paidconsultantsto Pfizer.JenniferM.Stephens,CaitlynT.Solem,andCourtney JohnsonareemployeesofPharmeritInternationalandwere paidconsultantstoPfizerinconnectionwiththisstudy. Cyn-thiaMacahiligisan employeeofMedicalData Analytics, a subcontractortoPharmeritInternationalforthisproject.Wing YuTang,RichardChambers,SeemaHaider,andMariaLavínea NovisdeFigueiredoareemployeesofPfizer.

Conﬂicts

of

interest

Theauthorsdeclarenoconﬂictsofinterest.Thisstudywas sponsoredbyPﬁzer.

Acknowledgments

Clinicalexpertsinvolvedintheoriginalstudydesign,which was adapted to Brazil: United Kingdom: Dilip Nathwani, Wendy Lawson; Germany: Christian Eckmann; France: Eric Senneville; Spain: Emilio Bouza; Italy: Giuseppe Ippolito; Austria: Agnes Wechsler Fördös; Portugal: Germano do Carmo;Greece:GeorgeDaikos;Slovakia:PavolJarcuska;Czech Republic:MichaelLips,MartinaPelichovska;andIreland:Colm Bergin.

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