Changes in Staphylococcus aureus susceptibility across Latin America between 2004 and 2010

The

Brazilian

Journal

of

INFECTIOUS

DISEASES

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

Original

article

Changes

in

Staphylococcus

aureus

susceptibility

across

Latin

America

between

2004

and

2010

Elvira

Garza-González

_,

_Michael

_Joseph

_Dowzicky

a_{DepartmentofMicrobiology,FacultaddeMedicina.UniversidadAutónomadeNuevoLeón,MonterreyNuevoLeón,Mexico} b_{PfizerInc.,Collegeville,PA19426,USA}

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Received28February2012 Accepted9August2012 Availableonline1January2013

Keywords: Tigecycline Antimicrobialsurveillance LatinAmerica Staphylococcusaureus

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TheTigecyclineEvaluationandSurveillanceTrialisaglobalsurveillancestudy monitor-ing the efficacyoftigecyclineand comparatorsagainstclinically importantpathogens. Between2004and2010,3126isolatesofStaphylococcusaureuswerecollectedfrom66 cen-tersin13countriesinLatinAmerica;ofthese,1467(46.9%)wereresistanttomethicillin. ThemaincontributorsofS.aureusisolateswereMexico(n=846),Argentina(n=740),and Colombia (n=445). Themethicillin-resistantS.aureus ratewasgreaterthan50%infive countries,thehighestreportedinPuertoRico(73.9%).Methicillin-resistantS.aureusrates acrossLatinAmericarangedfrom40.1%to50.6%overthestudyperiod.AllS.aureus iso-latesweresusceptibletolinezolidandvancomycin,while100%ofmethicillin-susceptibleS. aureusisolatesand99.8%ofmethicillin-resistantS.aureusisolatesweresusceptibleto tige-cycline.Bothmethicillin-susceptibleS.aureusandmethicillin-resistantS.aureuswerehighly susceptibleto minocycline (99.2%and97.0%, respectively). LatinAmerican methicillin-susceptibleS.aureuswerehighlysusceptibletolevofloxacin(94.6%)whileonly16.2%of methicillin-resistantS.aureuswerelevofloxacin-susceptible.Thisstudyshowsthat line-zolid,vancomycin,andtigecyclineareallhighlyactiveagainstS.aureusfromLatinAmerica, regardlessofmethicillinresistance.

©2013ElsevierEditoraLtda.Allrightsreserved.

Introduction

Staphylococcusaureusisacommoncomponentofthehuman bacterialflora,andcanexistbothasaharmlesscolonizerand asanactiveinfectivepathogen.S.aureusmaycauseanumber ofinfections,includingskinandsofttissueinfections,bone, joint and implant infections, pneumonia, septicemia, and toxicshocksyndrome.1 _{S.aureusisanimportantpathogen}

dueinpart tothe spreadofantimicrobialresistant strains, normally defined as methicillin-resistant S. aureus (MRSA);

∗ _{Correspondingauthor.Tel.:+528183294166.}

E-mailaddress:elvira [email protected](E.Garza-González).

these strains are often multidrug-resistant (MDR) and are associatedwithincreasedmorbidity,mortality,andtreatment costs.2–4

MRSA is the leading cause of nosocomial infections in LatinAmerica, andcommunity-based infectionsassociated withMRSAareincreasinginfrequency.5_SeveralLatin

Amer-ican centers participate in long-term surveillance studies suchasRESISTNET,SENTRY,T.E.S.T.[Tigecycline Evaluation andSurveillanceTrial],andZAAPS[ZyvoxAnnualAppraisal of Potency and Spectrum]. However, the real extent and importance ofMRSA infections inthe region are not fully

1413-8670/$–seefrontmatter©2013ElsevierEditoraLtda.Allrightsreserved. http://dx.doi.org/10.1016/j.bjid.2012.08.017

14

understoodasalargeproportionoftheregion’spopulation receives medicalcarefromsmall healthcarecenterswhich donothavetheresourcestocontributedatatosurveillance studies.6

SurveillancestudiessuchasT.E.S.T.areessentialin moni-toringchangesinthedistributionandprevalenceofimportant pathogenssuchasMRSA.Inanattempttobetterunderstand susceptibilitypatternsamongS.aureuscollectedacrossLatin America,weexamineanddescribeherechangesininvitro sus-ceptibilityamongisolatesofS.aureusandMRSAcollectedin LatinAmericaaspartofT.E.S.T.between2004and2010.Data aredescribedfortheregionaswellasforindividualcountries, bothlongitudinallyandoverthecompletecourseofthestudy period.Thisreportbuildsuponthesummaryofantimicrobial resistanceamongGram-positiveandGram-negativeisolates collectedinLatinAmericabetween2004and2007published byRossietal.7

Methods

Bacterialisolates

Bacterial isolates were collected in 13 Latin American countriesasapartofT.E.S.T.between2004and2010(2010data areincomplete,assomecentershadnotyetprovidedisolates atthetimeofwriting).Inthismanuscript,weexamine iso-latesofS.aureuscollectedinArgentina(12centers),Brazil(3 centers),Chile(5centers),Colombia(14centers),ElSalvador(1 center),Guatemala(4centers),Honduras(2centers),Jamaica (1center),Mexico(14centers),Nicaragua(1center),Panama (2centers),PuertoRico(1center),andVenezuela(6centers). Thedegreeofparticipationamongthe66centers contribut-ingisolatestothisstudywasasfollows:1centercontributed inall6years(Mexico);6centerscontributedin5years (Mex-icoandArgentina,2each;BrazilandChile,1each);6centers contributedin4years(Argentina,4;GuatemalaandChile,1 each);8centerscontributedin3years(Argentina,Mexico,and Venezuela,2each;BrazilandPanama,1each);25centers con-tributedin2years;and20centerscontributedinasingleyear only.

Eachparticipatingcenterwasrequiredtocollect25isolates ofS.aureusdeterminedbylocalcriteriatobeofclinical signif-icance.Onlyasingleisolateperpatientwasadmittedintothe study.Isolateinclusionwasindependentofage,sex,and/or previousmedicalhistory.Acceptableisolatesourcesincluded urine(limitedtonomorethan25%ofallisolates),blood, respi-ratory tract,skin, wound,and fluids from originallysterile bodysites.

Antimicrobialsusceptibility

Minimum inhibitory concentrations (MICs) for all isolates weredeterminedlocallyusingbrothmicrodilution method-ology (Sensititre® _{plates [TREK Diagnostic Systems, West} Sussex,England]orMicroScan®_{panels[Siemens,Sacramento,} CA,USA])asdescribedintheguidelinespublishedbythe Clin-icalandLaboratoryStandardsInstitute(CLSI).8_{Antimicrobial}

susceptibilitywasdeterminedaccordingtoCLSIinterpretive

criteria.9 _{S.aureusATCC29213wasusedforqualitycontrol}

studies.

The T.E.S.T. antimicrobial panel for S. aureus included the followingantimicrobial agents:amoxicillin-clavulanate, ampicillin,ceftriaxone,imipenem(MicroScan®_only), levoflox-acin, linezolid, meropenem (Sensititre® _{only), minocycline,} penicillin, piperacillin-tazobactam, tigecycline, and van-comycin.Dataforbeta-lactamantimicrobialsarenotincluded inthismanuscriptduetotheirinactivityagainstMRSA.

Isolatecollectionandtransportwerecoordinatedby Lab-oratories International for Microbiology Studies, a division ofInternationalHealthManagementAssociates,Inc.[IHMA, Schaumburg,IL,USA]).IHMAwerealsoresponsibleforidentity confirmationaswellasthedevelopmentandmanagementof acentralizeddatabaseforallisolates.

Results

Atotalof3126isolatesofS.aureuswerecollectedacrossLatin Americabetween2004and2010;1467(46.9%)wereidentified asmethicillin-resistant(Table1).ThegreatestnumbersofS. aureusisolateswerecontributedbyMexico(n=846),Argentina (n=740),andColombia(n=445).MRSAprevalencereached50% or moreinfivecountries,withthe highestratereportedin PuertoRico(73.9%).

S.aureusnumberswerelower in2010than inmost pre-ceding years as 2010 datawere incomplete atthe timeof writing.YearlyMRSAratesrangedfrom40.1%to50.6%across LatinAmerica duringthestudy intervalwithno noticeable geographicaltrendsseen(datanotshown).Largevariations inMRSAprevalencewere noticedinseveralcountries from yeartoyear,mostnotablyMexico(24.1–80.0%)andVenezuela (19.0–69.8%).

All S. aureus isolates in this study were susceptible to linezolidandvancomycin.Susceptibilitytotigecyclineacross LatinAmericawasalsoveryhigh:100%ofMSSAisolateswere tigecycline susceptiblewhile only3isolates ofMRSA were non-susceptible. Of the three tigecycline non-susceptible isolates,two(collectedinElSalvadorin2009) hada tigecy-clineMICof2mg/Lwhilethethird(collectedinHondurasin 2009)hadatigecyclineMICof1mg/L.Allthreeisolateswere alsonon-susceptibletolevofloxacin.Dataforlinezolid, van-comycin,andtigecyclinearenotpresentedintableformhere. Longitudinalinvitroactivityforlevofloxacinand minocy-cline againstMSSAandMRSAfromLatinAmericabetween 2004 and 2010 are listed in Table 2. Although 94.6% of MSSA isolates were susceptible to levofloxacin,only 16.2% of MRSA isolates were levofloxacin-susceptible during this period. MSSA susceptibility to levofloxacin was high but decreased from 100% in2004 to91.2% in2010. MRSA sus-ceptibilitytolevofloxacinwasnotablylower,rarelyexceeding 40%inanycountryinasingleyear;overthecollectionperiod, MRSAsusceptibilitywasextremelylow(≤6.4%)inBrazil,Chile, El Salvador,GuatemalaHonduras,and Mexico. While levo-floxacinsusceptibilityinArgentinadecreasedamongMSSA isolates (from 100% in2004 to82.4% in 2010),it increased amongMRSAisolates(from3.6%in2004to34.4%in2009). MRSAsusceptibilityacrossLatinAmericaincreasedfrom3.4%

Table1–NumbersofisolatesofStaphylococcusaureusandmethicillin-resistantS.aureus(MRSA)acrossLatinAmerica between2004and2010.

Country Year S.aureus(n) MRSA

n % Argentina 2004 64 28 43.8 2005 158 72 45.6 2006 56 26 46.4 2007 149 74 49.7 2008 174 86 49.4 2009 118 64 54.2 2010 21 4 19.0 Combined 740 354 47.8 Brazil 2005 49 30 61.2 2006 25 15 60.0 2007 25 10 40.0 2008 61 35 57.4 2009 80 36 45.0 2010 1 1 – Combined 241 127 52.7 Chile 2005 38 15 39.5 2006 40 25 62.5 2007 72 57 79.2 2008 45 21 46.7 2009 48 32 66.7 Combined 243 150 61.7 Colombia 2005 6 2 – 2006 72 40 55.6 2007 21 7 33.3 2008 163 61 37.4 2009 124 45 36.3 2010 59 10 16.9 Combined 445 165 37.1 ElSalvador 2009 34 19 55.9 Combined 34 19 55.9 Guatemala 2004 1 1 – 2006 37 23 62.2 2007 28 21 75.0 2008 27 22 81.5 2009 88 53 60.2 Combined 181 120 66.3 Honduras 2006 9 4 – 2007 13 2 15.4 2009 39 23 59.0 Combined 61 29 47.5 Jamaica 2006 25 4 16.0 Combined 25 4 16.0 Mexico 2005 15 12 80.0 2006 168 73 43.5 2007 112 27 24.1 2008 272 107 39.3 2009 212 94 44.3 2010 67 44 65.7 Combined 846 357 42.2 Panama 2006 25 11 44.0 2007 24 6 25.0 2008 26 10 38.5 2009 21 4 19.0 Combined 96 31 32.3 PuertoRico 2006 23 17 73.9

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Table1(Continued)

Country Year S.aureus(n) MRSA

n % Combined 23 17 73.9 Venezuela 2006 21 4 19.0 2007 47 11 23.4 2008 29 15 51.7 2009 86 60 69.8 2010 4 2 – Combined 187 92 49.2 LatinAmericaa _{2004 65 29 44.6} 2005 266 131 49.2 2006 505 244 48.3 2007 491 215 43.8 2008 797 357 44.8 2009 850 430 50.6 2010 152 61 40.1 Combined 3126 1467 46.9

Yearsforwhichnoisolateswereprovidedarenotlisted;%valuesarenotdisplayedwherethenumbersofisolatesofS.aureuswere<10.

a _{IncludesNicaragua(Nicaraguaisnotlistedseparatelyasonly4isolatesofS.aureus(2ofwhichwereMRSA)werecollected,allin2006).}

in2004to20.7%in2008butthendecreasedto8.2%in2010 (Table2).

MSSAsusceptibilitytominocyclinewashighacrossLatin America (99.2%), the lowest rate being reported in Brazil (95.6%).MRSAsusceptibilitytominocyclinewasonlyslightly lower(97.0%)thantheMSSAsusceptibilityrate.Minocycline non-susceptibleMRSAwerereportedamongallLatin Amer-ican countries with the exceptions of Chile, El Salvador, Honduras, Panama, and Puerto Rico. The lowest levels of minocycline-susceptibleMRSAwerereportedinBrazil(88.2%) andColombia(92.7%)(Table2).

Discussion

Afteraperiodofincreaseinthe1990sand2000s,the preva-lenceofMRSAhasdeclinedinsomeregionsinrecentyears.10

Picaoet al.11 _{reported on the prevalenceofMRSAin Latin}

Americabetween1997and2006aspartoftheSENTRYstudy. They found that more than one-third ofS. aureus isolates (37.3%)weremethicillin-resistant,increasingsignificantlyin prevalencefrom33.8%in1997to40.2%in2006(p=0.007).Data from thecurrent study suggest thatthis increase inMRSA levelsinLatinAmericahashalted:MRSAnumbersremained relativelystablebetween2004(44.6%)and2010(40.1%).

Rossietal.7_{previouslyreportedonratesofantimicrobial}

resistanceinLatinAmericaamongS.aureus(aswellasother importantpathogens)between2004and2007aspartofT.E.S.T. TherehasbeenlittlechangeinMRSAprevalencesincethis previousstudy:Rossietal.reported48.3%MRSAinLatin Amer-icabetween 2004and 2007,comparedwith 46.9%reported inthecurrent studybetween 2004and 2010.Two notewor-thychanges were observedbetweenRossiet al.’s dataand thecurrentstudy:inColombia,MRSAdecreasedfrom53.8% to37.1%,whileMRSAincreasedinVenezuelafrom19.0%to 49.2%.Thesechangescouldbedueinparttorelativelysmall

sample sizes collected inthese countries during the early yearsoftheT.E.S.T.study.Anotherimportantfactorcouldbe contributions from differentcentersover the courseofthe studyperiod:66centerscontributeddatatothecurrentstudy comparedto33centersforthe2008reportbyRossi.

InarecentstudyonLatinAmericanMRSA,Reyesetal.12

reported on the prevalence of MRSA in four countries, includingColombiaandVenezuela,between2006and2008. Comparedwiththecurrentstudy,theauthorsreportedhigher ratesofMRSAinColombia(45%comparedwith37.1%reported here)butlowerratesinVenezuela(26%comparedwith49.2%). These differencesaremostlikelyduetorealdifferencesin localprevalenceofMRSA:Saderetal.13showedthatthereis considerablevariationinMRSAratesamonghospitalsinthe samecountry aswellasamongcountriesinLatinAmerica. Thesediscrepanciescouldalsobedueinparttothecollection ofrelativelylownumbersofisolatesinthesetwocountries: only69and318MRSAisolateswereidentifiedfromVenezuela andColombia,respectively,byReyesetal.12_{whileonly92and}

165isolates(respectively)werecollected inT.E.S.T.between 2004and2010.

Thegoodactivityoftigecycline,linezolid,andvancomycin againstMRSAreportedhereissupportedbyotherresearchin LatinAmerica.Galesetal.13 _{reported100%susceptibilityto}

tigecycline,vancomycin,andlinezolidamong217 oxacillin-resistantS.aureusisolatescollectedacrossLatinAmericaas partoftheSENTRYstudyduring2000–2002.Inasubsequent SENTRYreport,Saderetal.(2009)14_{showedthat>99.9%ofS.}

aureus isolatescollected inLatin America betweenJanuary 2003 and December2008 were susceptibletolinezolid and vancomycin.Fernández Canigiaetal.15 _reported100%

tige-cyclinesusceptibilityamong878clinicalisolatesofS.aureus from Argentina betweenNovember 2005 and October2006 regardlessofmethicillinresistance.Casellasetal.16_reported

anMIC90 of0.25mg/Lfortigecyclineagainst223isolatesof S. aureus collected in nine centers across Argentina,while

b r a z j i n f e c t d i s . 2 0 1 3; 1 7(1) :13–19

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Argentina Brazil Chile Colombia Guatemala Mexico Panama Venezuela LatinAmerica

MSSA MRSA MSSA MRSA MSSA MRSA MSSA MRSA MSSA MRSA MSSA MRSA MSSA MRSA MSSA MRSA MSSA MRSA

Levofloxacin 2004 100 3.6 – – – – – – – – – – – – – – 100 3.4 2005 95.3 15.3 100 10 100 0.0 – – – – – 0.0 – – – – 97.0 10.7 2006 93.3 26.9 100 6.7 93.3 8.0 93.8 7.5 100 4.3 93.7 5.5 85.7 54.5 94.1 – 94.3 13.9 2007 96.0 36.5 93.3 10 93.3 0.0 92.9 – – 0 95.3 7.4 100 – 97.2 36.4 96.0 19.1 2008 88.6 40.7 92.3 2.9 95.8 0.0 98.0 34.4 – 0 93.9 8.4 87.5 20.0 92.9 40.0 93.6 20.7 2009 94.4 34.4 95.5 2.8 93.8 3.1 100 31.1 100 0 87.3 6.4 88.2 – 100 40.0 94.3 15.8 2010 82.4 – – – – – 100 10.0 – – 78.3 4.5 – – – – 91.2 8.2 2004–2010 93.5 29.7 95.6 5.5 95.7 2.0 98.2 25.5 100 0.8 91.8 6.4 90.8 35.5 96.8 38.0 94.6 16.2 Minocycline 2004 100 96.4 – – – – – – – – – – – – – – 100 96.6 2005 100 100 94.7 96.7 100 100 – – – – – 100 – – – – 99.3 99.2 2006 100 100 90.0 80.0 100 100 100 100 100 100 100 100 100 100 100 – 99.6 98.4 2007 100 97.3 100 100 100 100 100 – – 100 98.8 100 100 – 100 100 99.6 99.1 2008 100 98.8 96.2 71.4 100 100 99 85.2 – 95.5 99.4 94.4 100 100 100 100 99.3 92.4 2009 100 96.9 95.5 97.2 100 100 98.7 93.3 100 98.1 99.2 100 94.1 – 96.2 98.3 98.6 98.1 2010 100 – – – – – 95.9 100 – – 100 97.7 – – – – 97.8 98.4 2004–2010 100 98.3 95.6 88.2 100 100 98.6 92.7 100 98.3 99.4 98.0 98.5 100 98.9 98.9 99.2 97.0

a _{AllisolatesofS.aureusweresusceptibletolinezolidandvancomycin,sodatafortheseantimicrobialsarenotlistedhere.Only3(0.1%)tigecyclinenon-susceptibleisolateswerecollected(1in}

Hondurasand2inElSalvador,allin2009),sotigecyclinedataarenotlistedhere.

b _{DatawereonlycontributedinasingleyearforElSalvador(2009:S.aureus,n=34;MRSA,n=19),Jamaica(2006:S.aureus,n=25;MRSA,n=4),Nicaragua(2006:S.aureus,n=4;MRSA,n=2)andPuerto}

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Silva-Sanchezet al.17 _{recounted anMIC}

90 of0.125mg/Lfor tigecyclineagainst482MRSAisolatesfromMexico.Inaglobal reviewofGram-positivepathogens(includingLatinAmerica) aspartoftheZAAPS program,Jones etal.18 _didnotreport

anylinezolidresistanceamong3240S.aureusisolatesin2008. MinocyclinealsoperformedwellagainstMRSAinthecurrent study,aresultsupportedbyReyesetal.12_whoreported

low-levelminocyclineresistance(1%;8/651)amongMRSAisolates collectedinColombia,Ecuador,Peru,andVenezuelabetween 2006and2008.

Vancomycin is widely used in Latin America for the treatmentofMRSAinfections.19_{WhilenoVRSAisolates(or}

vancomycin-intermediateMRSA[VISA]isolates)were identi-fiedinthecurrentstudy,bothMRSAandMSSAisolateswith vancomycinMIC90sof2mg/L(theupperlimitofvancomycin susceptibility)wereobserved.IsolatesofMRSAwithreduced susceptibilitytovancomycinhavebeenidentifiedpreviously acrossLatinAmerica.20–24_{Adecreaseintheactivityof}

van-comycininclinicalsettingsisseen bysomeasacause for concernStefani and Goglio,2 _{andalternative approaches to}

MRSAtreatmentmustbemadeavailableifVISAorVRSA fre-quencyincreasesintheregion.

Onepotentialsourceforerrorinanysurveillancestudyis inconsistentmethodologiesbeingusedindifferentcenters. AllMICsinT.E.S.T.weredeterminedlocallyusingCLSI-defined broth microdilution methodology (Sensititre® _{plates [TREK} Diagnostic Systems, West Sussex, England] or MicroScan® panels[Siemens,Sacramento,CA,USA]).8_{Antimicrobial}

sus-ceptibilitywasdeterminedusingCLSIinterpretivecriteria.9_In

ordertoensureconsistentresultsbetweencentersandreduce thepotentialforexperimentalerror,standardizedprocedures wereutilized atallparticipating centers.These includethe useofthesamematerials(MICpanels,microdilutionbroth, inoculators)aswellasprocedures(qualitycontrol[QC] proce-dures,QCranges)asthecentrallab,asdetailedbyCLSI.8,9_QC

strainS.aureusATCC29213wasculturedoneachdayofMIC testingtoensurethatcollectedMICvaluesfellintoacceptable QCranges.

Surveillancestudiesareofteninfluencedbystudybiases Bax et al.25 _{Although66 centers acrossLatin America}

par-ticipatedinthis study,onlyonecentercontributed isolates inallsixyearsofthestudy.Theseinconsistenciesincenter participationwillmostlikelyhaveinfluencedthelongitudinal susceptibilitiesreportedhere.

Conclusions

SurveillancestudiessuchatT.E.S.T.areessentialtoolsinour effortstomonitorthespreadofproblematicpathogenssuch asMRSA,bothregionallyandglobally.Surveillanceprovides informationcritical to healthcareprofessionals formaking informeddecisionsregardingappropriateantimicrobial ther-apyto preventand treatinfection, described succinctly by Johnson10_{as‘informationforaction’.Resultsfromthe}

Tigecy-clineEvaluationandSurveillanceTrial,whichhasbeenactive since2004,indicatethatlinezolid,vancomycinandtigecycline areallhighlyactiveagainstmethicillin-resistantS.aureus iso-latesfromtheLatinAmericaregion.

Conflict

of

interest

MichaelJDowzickyisanemployeeofPfizerInc.

Acknowledgements

ThisstudywassponsoredbyPfizerInc.

MedicalwritingsupportwasprovidedbyRodTaylorPhDat MicronResearchLtd,Chatteris,UKandwasfundedbyPfizer Inc.MicronResearchLtdalsoprovideddatamanagement ser-viceswhichwerefundedbyPfizerInc.

ElviraGarza-GonzalezisaninvestigatorintheT.E.S.T. pro-gram. Noauthors were paidfor their contributionsto this manuscript.

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