The
Brazilian
Journal
of
INFECTIOUS
DISEASES
w w w . e l s e v i e r . c o m / l o c a t e / b j i d
Review
article
Extended
spectrum
-lactamase
producers
among
nosocomial
Enterobacteriaceae
in
Latin
America
Manuel
Guzmán-Blanco
a,∗,1,
Jaime
A.
Labarca
b,
Maria
Virginia
Villegas
c,
Eduardo
Gotuzzo
d,
On
behalf
of
the
Latin
America
Working
Group
on
Bacterial
Resistance
2aHospitalPrivadoCentroMédicodeCaracasandHospitalVargasdeCaracas,Caracas,Venezuela
bDepartmentofInfectiousDiseases,SchoolofMedicine,PontificiaUniversidadCatólicadeChile,Santiago,Chile cBacterialResistanceGroup,InternationalCenterforMedicalResearchandTraining(CIDEIM),Cali,Colombia dUniversidadPeruanaCayetanoHeredia,Lima,Peru
a
r
t
i
c
l
e
i
n
f
o
Articlehistory:
Received10May2013
Accepted29October2013
Availableonline3January2014
Keywords: Escherichiacoli Klebsiella LatinAmerica Bacterialresistance
a
b
s
t
r
a
c
t
To review the epidemiology of nosocomial extended spectrum -lactamase-producing
EnterobacteriaceaeinLatinAmerica,asystematicsearchofthebiomedicalliterature(PubMed)
wasperformedforarticles publishedsince2005.Ratesofnosocomialinfectionscaused
by extended spectrum -lactamase-producing Enterobacteriaceaein Latin America have
increasedsince2005.Upto32%ofEscherichiacoliandupto58%ofKlebsiellapneumoniae
isolatesareextendedspectrum-lactamase-positive,ratesthatarehigherthaninother
worldregions.Fromaregion-wideperspective,11–25%ofE.coliisolatesand45–53%ofK.
pneumoniaeisolateswerenonsusceptibletothird-generationcephalosporins.Atthe
coun-trylevel,therewasawiderangeinEnterobacteriaceaeresistanceratestothird-generation
cephalosporins,withespeciallyhighratesofresistancetoE.coliinGuatemala,Honduras,
andMexico,andhighresistanceratestoKlebsiellaspp.inArgentina,Brazil,Chile,Guatemala,
Honduras,andParaguay.Susceptibilityofextendedspectrum-lactamase-producing
Entero-bacteriaceae to cefepime, fluoroquinolones, ampicillin/sulbactam, aminoglycosides, and
piperacillin/tazobactamhasalsobeencompromised,leavingthecarbapenems,tigecycline,
andcolistinastheonlyantibioticswith>90%susceptibilityrates.Thereisasteadyincrease
intheprevalenceandtypesofextendedspectrum -lactamasesproducedby
Enterobac-teriaceae isolatesinLatinAmericanhospitals(particularlyCTX-Ms), suggestingendemic
conditions overlaid byclonaloutbreaks.Appropriate treatment decisionsand infection
controlstrategiesinformedbysurveillanceofregionalandlocalsusceptibilitiesand
mech-anismsofresistancearerequiredtomitigatethismajorpublichealthconcern.
©2014 ElsevierEditoraLtda.Allrightsreserved.
∗ Correspondingauthor.
E-mailaddress:mibeli03@gmail.com(M.Guzmán-Blanco).
1 TheauthorsdedicatethisworktothememoryofJoséMaríaCasellas.
2 SeeAppendixAforthemembersoftheWorkingGroup.
1413-8670/$–seefrontmatter©2014 ElsevierEditoraLtda.Allrightsreserved.
Introduction
Healthcare-associatedinfections(HAIs)areparticularly
chal-lengingindevelopingcountriessuchasthoseofLatinAmerica
owingtotheir farhigher rateofoccurrence thanin
devel-opedcountries.Forinstance,theWorldHealthOrganization
reported that the pooled prevalenceof hospital-wideHAIs
between1995and2010inlow-andmiddle-incomecountries
was 10.1 per 100 patients (95% confidence interval [CI],
8.4–12.2),whichcomparesunfavorablywiththe
correspond-ing rate in high-income countries (7.6 episodes per 100
patients;95%CI,6.9–8.5).1MostHAIsindevelopedand
devel-opingcountriesarebyGram-negativebacteria,predominantly
speciesandsubspeciesfromtheEnterobacteriaceaefamily
fol-lowedbynonfermenterssuchasPseudomonasaeruginosaand
Acinetobacterbaumannii.1–4Thecapacityofhealthcare
profes-sionalstomanagenosocomialinfectionsbyEnterobacteriaceae
hasdiminished over the last decade because ofthe
emer-genceandwidespreaddisseminationofmultidrug-resistant
phenotypes.2,5–8
Production of -lactamases is the primary
mecha-nism of -lactam resistance in these pathogens.9–15 ESBL,
extended spectrum -lactamase (ESBLs) can confer
resis-tance to penicillins, first-, second-, and third-generation
cephalosporins, and aztreonam (but not the cephamycins
suchascefoxitinorcarbapenems),andareusuallyinhibited
by -lactamase inhibitors such as clavulanic acid.15 Most
ESBLscan alsohydrolyzefourth-generation cephalosporins
(e.g., cefepime or cefpirome).16,17 It is important to note
that AmpC -lactamases differ from typical ESBLs in that
AmpC -lactamases, besides hydrolyzing third-generation
cephalosporins,arenotinhibitedby-lactamaseinhibitors.15
Furthermore, Enterobacteriaceae harboring ESBLs are often
co-resistant to fluoroquinolones, aminoglycosides, and
trimethoprim/sulfamethoxazole.15,18 Thus, infections by
thesemultidrug-resistantpathogensareamajorpublichealth
threat,astherearelimitedtreatmentoptionsavailable.
Thepurposeofthisreviewistoprovideanupdated
epi-demiology ofESBL-producing Enterobacteriaceae inthe Latin
Americanhospitalsetting,withafocusonantimicrobial
sus-ceptibilitiesofEscherichiacoliandKlebsiellapneumoniaestrains
throughouttheregion.Weincludeinthisreviewdatafromthe
Spanish-andPortuguese-speakingcountriesoftheAmericas,
includingMexico.
Background:
emergence
of
extended
spectrum
-lactamase-producing
Enterobacteriaceae
in
Latin
America
before
2005
Duringtheperiodfrom1987to1989,K.pneumoniae
express-ing sulfhydryl variant (SHV)-5 and SHV-2 were responsible
forinfectionoutbreaksinaBuenosAiresintensivecareunit
(ICU).14 Retrospective analysis of a lyophilizedstrain ofK.
pneumoniae recovered in 1982 from the urine of a patient
withanindwellingurinarycatheterdetectedSHV-5,making
thistheearliestdetectedESBL-producingbacteriuminSouth
America.14,19Cefotaxime-resistant(CTX-M)-lactamasewas
first described in an outbreak of neonatal infection with
Salmonellatyphymuriumduring1989inArgentina,Bolivia,and
Paraguay.14Furtheroutbreaksofinfectionsinneonatescaused
by ESBL-producing Klebsiella spp.were reportedin the late
1990sinMexicoandBrazil.20,21
By the late 1990s, ESBL expression by Enterobacteriaceae
in LatinAmerican hospitalsbecameendemic. During
SEN-TRYantimicrobialsurveillanceconductedbetween1997and
2002, the prevalence of Klebsiella spp. expressing ESBLs in
bloodculturesfromhospitalizedpatientswasgreaterinLatin
America than in Europe and North America (43% vs. 22%
and 6%,respectively,p<0.001).9 SENTRYdataforurine
iso-latesrevealedthat∼45%ofKlebsiellaspp.exhibitedanESBL
phenotypein2000(comparedwith∼30%during1997–1999)
and∼5%ofE.coliexhibitedanESBLphenotypeduringboth
testingperiods.13ThepercentageofEnterobacteriaceae
produc-ingESBLswasalsoveryhighinBrazilianhospitals(SENTRY,
1997–1999),with50%ofallK.pneumoniaeisolatesand9%ofall
E.coliisolatessuspectedofharboringESBLs.22Overaslightly
latertimeframe,findingsoftheMeropenemYearly
Suscepti-bilityTestInformationCollection(MYSTIC)study(1997–2003)
showedthat52%ofK.pneumoniaeisolatesfromLatinAmerica
(vs.12%fromNorthAmerica), 18%ofE.coliisolates(vs.8%
fromNorthAmerica),and6%ofProteusmirabilisisolates(vs.
4%fromNorthAmerica)wereESBL-positive.23
CTX-M-type -lactamases eventually replaced TEM and
SHVvariantsasthemostcommontypeofESBLglobally.18,24
In2000,CTX-M-2wasthemostprevalenttypeofESBLinLatin
America(especiallyinthesouthernpartofthecontinent),25
and in 2002,CTX-M-12from a strain ofK.pneumoniae was
detected in Colombia, representing the first description of
a CTX-M in this country.26 While ESBLs are found
pre-dominantly in Klebsiella spp. and E. coli, they have also
beendescribedinothergeneraofEnterobacteriaceaeincluding
speciesofCitrobacter,Serratia,Proteus,Morganella,Salmonella,
andEnterobacter.14
Methods
Toreviewthepublishedclinicaldatarelating to
epidemiol-ogyofESBL-producingEnterobacteriaceaeintheLatinAmerican
hospital setting,a systematicsearch of the biomedical
lit-erature wasconducted.Medline(viaPubMed)wassearched
limitedbythedates1January2005to15July2013forarticles
usingthefollowingtermsandBooleanlogic:(Extended
spec-trumbetalactamaseORESBL)AND(EnterobacteriaceaeORcoli
ORKlebsiellaORShigellaORSalmonellaORProteus)AND(“Latin
America”OR“SouthAmerica”OR“CentralAmerica”OR
Mex-icoORGuatemalaORHondurasORNicaraguaOR“CostaRica”
ORCubaOR“DominicanRepublic”ORPanamaORColombia
ORVenezuelaORGuyanaORSurinameOR“FrenchGuiana”OR
BrazilOREcuadorORPeruORBoliviaORParaguayORUruguay
ORChileORArgentina).Selectedadditionalreferenceswere
identifiedbyauthors.
Prevalence
and
type
of
extended
spectrum
-lactamases
Regionaldata
Severalregionalsurveillancestudiesmonitordrugresistance
Table1–Numberofstudysitesbycountryforkeysurveillancereports.
Country Surveillanceprogramandcollectionperiod
SMART27 SMART28 SMART29 SMART30 TEST31 TEST32 SENTRY33 PAHO34,a PAHO35,a
2004 2005 2008 2008–2009 2004–2006 2004–2010 2008–2010 2006 2009 Argentina 3 2 2 2 9 12 2 59 72 Bolivia 19 30 Brazil 3 2 5 1 1 3 4 Chile 2 2 2 2 5 2 Colombia 1 3 2 14 147 DominicanRepublic 1 1 14 14 Ecuador 1 1 21 22 ElSalvador 1 33 33 Guatemala 1 1 1 1 4 6 5 Honduras 2 4 7 Mexico 2 2 3 4 1 15 2 Nicaragua 1 10 11 Panama 1 1 1 1 2 24 24 Paraguay 8 21 Peru 1 2 22 40 PuertoRico 2 2 1 Venezuela 1 3 3 6 34 24
PAHO,Pan-AmericanHealthOrganization;SMART,StudyforMonitoringAntimicrobialResistanceTrends;TEST,TigecyclineEvaluationand SurveillanceTrial.
a IncludingonlycountriesreportingdataonEnterobacteriaceaeinhospitalsettings.
centersin eachcountry. Thenumberofcenters from each
country participating in surveillance efforts is shown in
Table1.27–35 According todatafromthe Studyfor
Monitor-ing Antimicrobial Resistance Trends (SMART), Tigecycline
Evaluation and Surveillance Trial (TEST), and Doripenem
InternationalSurveillanceNetwork(DISN),theprevalenceof
ESBL-producingK.pneumoniaewasfarhigherinLatinAmerica
thaninotherworldregions(Fig.1).8,27,28,31,36 Similarly,only
theAsia/PacificregionhadhigherratesofESBLproductionin
E.coli.8,27,28,31,36Furthermore,prevalenceofESBL-producing
E.coliand Klebsiellaspp.appearstohavesteadilyincreased
over the last decade (Table2).8,27–33,36 Agreater proportion
ofKlebsiella spp. than E. coliproduceESBLs, although ESBL
productionbyE.colihasincreasedsincetheperiodbefore2005.
50 45 40 35 30 25 20 15 10 12 6 3
SMART 2004 SMART 2005 TEST 2004-2006 SMART 2009-2010SMART 2004 SMART 2005 TEST 2004-2006 DISN 2007 Latin America
P
ercentage of isolates producing ESBLs
North America E. coli Europe Asia/Pacific Klebsiella spp. DISN 2007 20 16 26 7 2 14 12 14 8 7 23 19 17 22 16 44 44 8 13 13 8 8 9 5 28 28 23 27 4 8 2 5 0 * * * *
Fig.1–FrequencyofESBLproducersamongE.coliandK.pneumoniaeisolatesintheSMARTandTESTantimicrobial surveillanceprograms.8,27,28,31,36*UnitedStatesdataonly.DISN,DoripenemInternationalSurveillanceNetwork;ESBL,
extendedspectrum-lactamase;SMART,StudyforMonitoringAntimicrobialResistanceTrends;TEST,Tigecycline EvaluationandSurveillanceTrial.
Table2–Temporalprevalencesofhealthcare-acquiredESBL-positiveEnterobacteriaceaeinhospitalsofLatinAmerica.
Surveillanceprogram Collectionperiod Anatomicalcollectionsite ProportionESBL-positive (totalno.isolates)
E.coli Klebsiellaspp.
SMART27 2004 Intra-abdominal 12% 28%
SMART28 2005 Intra-abdominal 16%(395) 27%(121)
TESTa,31 2004–2006 Blood,respiratorytract,urine,
skin,wound,fluidsandother definedsources
14%(326) 44%(282)b
TEST32 2004–2010 Blood,respiratorytract,urine,
skin,wound,fluids
24%(3581) 35%(2962)b
DISN8 2007 Blood,respiratorytract,skin
andskinstructure,urine
14%(493) 44%(350)b
SMART29 2008 Intra-abdominal 27%(504) 38%(151)b
SMART30 2008–2009 Intra-abdominal 24%(1366) NR
SENTRY33 2008–2010 Blood,skinandsofttissue,
lowerrespiratorytract
25%(1517) 53%(1052)
SMARTc,36 2009–2010 Urine 23%
ESBL,extendedspectrum-lactamase;DISN,DoripenemInternationalSurveillanceNetwork;NR,notreported;SMART,StudyforMonitoring AntimicrobialResistanceTrends;TEST,TigecyclineEvaluationandSurveillanceTrial.
a Mostdatawerecollectedfromintensivecareunits. b K.pneumoniaeonly.
c Datacollectedfrom15sitesinLatinAmerica;countrieswheresiteslocatednotspecified.36
Country-specificdata
Surveillancestudies
In the SENTRY 2008–2010, SMART 2008–2009, and TEST
2004–2010reports,thefrequenciesofE.coliproducingESBLs
were highest inChile, Ecuador, Guatemala, Honduras,and
Mexico(Fig.2a).30,32,33AmongKlebsiellaspp.,ESBLphenotype
ratesof50% or greater were observedin Argentina,Brazil,
Chile,andHonduras(Fig.2b).32,33
Cohortstudies
As in the surveillance studies, independent cohort data
revealed that a greater proportion of K. pneumoniae than
E. coli clinical isolates produce ESBLs throughout the
con-tinent(Fig.3).37–48 Therange ofESBLproductionamongK.
pneumoniaeisolatesvariedfrom 24% (in Cuba, 2009–2010)44
to58% (in Curitiba, Brazil,2003–2004)46 whereas ESBL
pro-ductionamongE. coli isolatesvariedfrom 7%(in southern
Brazil)45to32%(inSonoro,Mexico,2008–2009).42Caremust
betakenwheninterpretingthesedatabecauseofinter-study
differenceswithrespecttothe time,method(i.e.,
consecu-tiveorrandom),andanatomicalsiteofsamplecollection,as
wellasthemicrobiological techniquesandstandardsused.
Nevertheless,data collected byindependentcohortstudies
on thefrequency ofESBL productionamongE. coliclinical
isolates (Fig. 3) compared favorably withdata collected by
SMART,SENTRY,and TEST(Fig.2a)forBrazil(range, 7–24%
vs. 13–17%, respectively), Mexico (16–32% vs. 38–48%) and
Venezuela (16–27% vs 15–30%). Regarding the frequency of
ESBLproductionamongK.pneumoniaeclinicalisolates,
gen-eral agreementwas observed between independentcohort
(Fig.3)and surveillancedata(Fig.2b)forBrazil(44–58%vs.
49–50%,respectively), and Mexico (27–36% vs. 25–33%),but
notVenezuela(46–48%vs.17%).Limitedprevalencedatawere
availableforBolivia (SantaCruzdelaSierra,2004)wherein
150–642(23%)consecutivelycollectedGram-negativeisolates
wereputativeESBLproducers,butthisstatisticencompassed
strains ofP.aeruginosa andAcinetobacterspp. inadditionto
Enterobacteriaceae.49
ThemolecularcharacteristicsoftheESBLisolatesdetected
insurveillancestudieswerenotdescribedinthose
publica-tions.MostofourknowledgeaboutspecificESBLscirculating
inLatinAmericanhospitalscomesfromindependentcohort
studies. Fig. 3 shows that CTX-Ms have infiltrated most
countriestovariousextents,withCTX-M-15commonlyfound
inthenorthernpartofthecontinent.Theendemicityof
CTX-M-15ischallengingbecausethisenzyme,unlikeotherESBLs,
canhydrolyzeceftazidime.50CTX-M-2wasthemostcommon
subtypeinArgentina (52%of50 ESBLproducers),and data
indicatedemergenceofCTX-M-15(38%)alongwith
CTX-M-8(2%)andCTX-M-9(6%).48SHVenzymes(particularlySHV-5
andSHV-12)werehighlyprevalentinMexico,Colombia,and
Brazil(Fig.3).
These prevalence findings are supported by results of
studies that examined the genotype distribution among
ESBLproducers.Of127ESBL-producingEnterobacteriaceae
iso-lated over one year from inpatients and outpatients at a
public teaching hospital at São Paulo, Brazil, blaCTX-M and
blaSHV were highly prevalent (in 34% and 63% of strains,
respectively).51 In Colombia (Bogota, 2003–2005),
computa-tional sequencing analysis revealed that CTX-M-12 (56%)
and SHV-12(33%)were themostprevalentESBLs produced
among177 K.pneumoniaeisolates harboringblagenes.52 In
Bolivia, blaCTX-M-2 (71%), and to a lesser extent blaCTX-M-43
(21%), were the most prevalent genes encoding ESBL
pro-ductionin150Gram-negativeclinicalisolatescollectedfrom
four hospitalsinSantaCruz delaSierra duringa4-month
period in 2004.49 In addition, blaPER-2 was reported among
31%of122ESBL+K.pneumoniaeisolatescollectedin10
hos-pitalsinChilein1998–2004(40%wereblaCTX-Mand13%were
80 70 60 50 40 30 20 10 0 18 60 39 50 49 59 60 51 19 73 33 25 39 17 Brazil Chile Colombia Dominican
Republic
Ecuador Guatemala Honduras
Honduras
Mexico Panama Venezuela 13 13 14 17 24 30 35 8 11 16 36 3031 40 48 41 38 5 16 30 15 6 80 70 60 50 40 30 20 10 0 Argentina Argentina SENTRY 2008-2010 TEST 2004-2010 P ercentage of K. pneumoniae
isolates producing ESBLs
P
ercentage of
E.
coli
isolates producing ESBLs
Brazil Chile Colombia Guatemala Mexico Panama Venezuela
SENTRY 2008-2010 SMART 2008-2009 TEST 2004-2010
A
B
Fig.2–NationalfrequenciesofESBLproducersamong(a)Escherichiacoliand(b)KlebsiellapneumoniaeisolatesinLatin Americanhospitals.30,32,33ESBL,extendedspectrum-lactamase;SMART,StudyforMonitoringAntimicrobialResistance
Trends;TEST,TigecyclineEvaluationandSurveillanceTrial.InSENTRY2008–2010report,onlythe4countrieswithhighest ratesofESBLproductionwerereported.
ineighthospitalsinCaracas,Venezuelain2009-2010weretype
PER.40
Antimicrobial
susceptibility
Regionaldata
Data on antimicrobial susceptibilities are reported for the
Latin American region by the SMART, TEST, and SENTRY
surveillance efforts, and for individual Latin American
countriesbyThePan-AmericanHealthOrganization(PAHO)
(seeTable1forcountriesparticipatingineacheffort).
From a regional perspective, E. coli strains were
more often susceptible (75–89%) to third-generation
cephalosporins than strains of K. pneumoniae (47–55%,
referring to strains that were not distinguished as ESBL+
or ESBL−).28–33 Susceptibilities of E. coli and K.
pneumo-niae to the fourth-generation cephalosporin cefepime
36% K. pneumoniae (n=92) 24% K. pneumoniae (n=228) 46% K. pneumoniae (n=416) 48% K. pneumoniae (n=63) 47% K. pneumoniae (n=17) 25% P. mirabilis (n=12) 24% E. coli (n=42) 58% K. pneumoniae (n=115) 44% K. pneumoniae (n=142) 7% E. coli (n=209) 8% P. mirabilis (n=25) 7% E. coli (n=193) 30% E. cloacae (n=67) 16% E. coli (n=146) 27% E. coli (n=406) 80% CTX-M-15 (n=54) 36% E. cloacae (n=87) 30% E. coli (n=80) 21% S. marcescens (n=83) 35% K. pneumoniae (n=102) 27% K. pneumoniae (n=78) 32% E. coli (n=239) 16% E. coli (n=460) 52% K. pneumoniae (n=31a) 11% K. pneumoniae (n=193) 4% P. mirailis (n=115) 3% E. cloacae (n=37) 1% E. coli (n=1120) 31% E. coli (n=39a) ESBL+ ESBL+ K. pneumoniae ESBL+ ESBL+ blaCTX-M-2 blaCTX-M-1 blaSHV blaTEM K. pneumoniae E. cloacae ESBL+ ESBL+ S. marcescens E. coli E.coli ESBL+ Enterobacteriaceae (K. pneuomoniae, E. cloacae, E. coli, and s. marcescens) ESBL+ Enterobacteriaceae (K. pneumoniae and E. coli) ESBL+ ESBL+ K. pneumoniae E.coli 0 20 40 60 80 100 0 20 40 60 80 100 0 20 40 60 80 67 95 42 11 100 0 20 17 40 60 80 86 100 0 20 40 60 80 100 blaCTX-M-15 blaSHV-12 blaCTX-M-15 blaSHV-5 blaCTX-M-1 blaSHV blaTEM blaSHV-5 Percentage Percentage Percentage Percentage Percentage blaCTX-M blaSHV blaTEM 86 89 6 33 31 30 Monterrey, Mexico 2006-200938 Sonora, Mexico 2008-200942 Maracaibo, Venezuela 2006-200747 Cuba 2009-201044 39 13 50 5 6 5 54 67 64 13 0 0 0 2 30 10
Ciudad Bolivar, Venezuela 201143
Rio de Janeiro, Brazil 201141
Caxias do Sul, Brazil 2003-200645
Curitiba, Brazil 2003-200446
Guadalajara, Mexico 2010-201139
76
85
Colombia, Carribean region37
Throughout Argentina 201048 83 Other 16% Enterobacterias (n=1235) 24% Enterobacterias (n=498) Caracas, Venezuela 2009-201040 54
Fig.3–RepresentationofthefrequencyofESBLproduction(no.ofisolatestested)andtypesofESBLsproducedby
EnterobaceriaceaeisolatedfromLatinAmericanhospitalsreporting>100isolates.37–47ThedistributionofESBLswasnot
availableforallstudiesreportingprevalencedata.Allisolateswereresistanttooxyimino-cephalosporins.ESBL,extended spectrum-lactamase.
third-generation cephalosporins. As expected,
suscepti-bility to third-generation cephalosporins and cefepime
was much lower among ESBL-positive E. coli and K.
pneu-moniae strains than among ESBL-negative or unspecified
isolates (Table 3).29–32 Antimicrobial co-resistance was a
recurring feature among these isolates, particularly those
expressing ESBLs. In SENTRY 2008–2010, E. coli (all
iso-lates)weremostsusceptibletothecarbapenems(99–100%),
amikacin (97–100%), piperacillin/tazobactam (82–94%),
and colistin (100%), whereas low rates of susceptibility to
ciprofloxacin (35–73%) were observed.33 Susceptibility of
Klebsiella spp. was appreciably lower than that of E. coli
to all of these drug classes, with susceptibility rates of
89–99% for carbapenems, 78–92% for amikacin, 49–81%
for piperacillin/tazobactam, and 95–99% for colistin across
fourcountries(Argentina,Brazil,Chile, andMexico).33Even
lower susceptibility rates across the commonly used drug
classes were observed for ESBL-producing E. coli and K.
pneumoniae isolates collected in SMART 2008, 2008–2009,
and TEST2004–2010.29,30,32 Althoughsusceptibilityof
ESBL-producing E. coli to carbapenems and tigecycline was
>95% in all of these studies, susceptibility to amikacin
(85–90%), piperacillin/tazobactam (74–80%), and
fluoro-quinolones (12–19%) dropped markedly.29,30,32 Likewise,
susceptibility ofESBL-producingK.pneumoniaeto
carbapen-ems (in TEST 2004–2010 and SMART 2008) and tigecycline
(in TEST 2004–2010) was high (≥89%), but
susceptibil-ity was low to amikacin (71–72%), levofloxacin (35–38%),
and piperacillin/tazobactam (34–40%) in both surveillance
studies.29,32
Country-specificdata
PAHO established a surveillance program in 2000 to
col-lect country-specificdataonselectedorganisms, bothfrom
nosocomialandcommunity-acquiredinfections.In2006and
2009, there was large variability in Enterobacteriaceae
Table3–Proportionofhealthcare-acquiredEnterobacteriaceaeisolatessusceptibletothird-generationcephalosporins
(andcefepime)inLatinAmericanhospitals.
Pathogen SMART200528 TEST2004–200631 TEST2004–201032 SMART200829 SMART2008–200930 SENTRY2008–201033
E.coli 83–84%(84%a) n=395isolates 82–89%(86%) n=326isolates 82%(94%) n=2711 non-ESBL isolates 96%(100%) n>50 non-ESBL isolates 94–95%(100%) n=1043 non-ESBL isolates 75–82%(84%) n=1517isolates 1%(28%) n=870ESBL isolates 2%–28%(7%) n>50ESBL isolates 1%-21%(12%) n=323ESBL isolates K.pneumoniae NR 53–55%(58%) n=282isolates 77%(88%) n=1917 non-ESBL isolates 96–97%(97%) n>50 non-ESBL isolates NR 47–55%(59%) n=1052 isolatesb 0%(0%) n=124ESBL K.pneumoniae isolates 1%(29%) n=1045ESBL K.pneumoniae isolates 2%–28%(7%) n>50ESBL K.pneumoniae isolates S.marcescens NR 77%(82%) n=124isolates 68%(84%) n=1126isolates NR NR NR
NR,notreported;SMART,StudyforMonitoringAntimicrobialResistanceTrends;TEST,TigecyclineEvaluationandSurveillanceTrial.
a Throughouttable,figuresinparenthesesareproportionssusceptibletocefepime,afourth-generationcephalosporin. b Klebsiellaspp.
and ceftazidime), evenafter accounting for countries with
smallisolatenumbers(Table4)34,35andfewcollectingcenters
(Table 1). In 2009, the resistance rate of E. coli to
third-generationcephalosporinswashighestinBolivia(37%)and
lowest in Nicaragua (0–0.5%; Table 4). PAHO data for K.
pneumoniaenosocomialisolates in2009showedhigh levels
ofresistancetothird-generationcephalosporins,consistent
withthehighprevalenceofESBL-producingstrainsinLatin
Americancountries.TheresistancerateofKlebsiellaspp.to
third-generationcephalosporinsin2009washighestinPeru
(66%)andlowestinNicaragua(0.3%).Ahighrateofresistance
tocefepimeinnosocomialisolatesofE.coliandK.pneumoniae
wasalsoreportedinPAHO2009data(Fig.4).35ThePAHOdata
forKlebsiellaspp.were similartofindings oftheAsociación
Panamericanade Infectología, showingthatthe proportion
ofcefotaxime-resistantstrainsrangedfrom17%(inEcuador
andPanama)to60%(inBrazil),resistanceratestoceftazidime
rangedfrom13%(inVenezuela)to40%(inArgentina,Brazil,
andParaguay),andresistancetocefepimerangedfrom10%
(inColombia)to50%(inArgentinaandBrazil).54
DatacollectedbytheSENTRYAntimicrobialSurveillance
Program between 2008 and 2010 reported country-specific
data in addition to regional data. They showed that the
susceptibility rate ofhealthcare-acquired E. coli isolates to
third-generationcephalosporinswaslowinMexico(52–53%)
andmodestinArgentina,Brazil,andChile(76–88%).33Again,
Table4–FindingsofthePan-AmericanHealthOrganization(PAHO)summarizingthefrequencyofnosocomial
Enterobacteriaceaeisolatesresistanttothird-generationcephalosporinsin2006and2009.34,35
Country %Resistance(totalno.isolates)
E.coli K.pneumoniae 2006 2009 2006 2009 Argentina 4(12001) 18(1659) 57(3278)a 58(1518) Bolivia 33(1079) 37(2923) 14–47(646)a 27–50(984) Colombia – 8-9(9607) – 30(3607) DominicanRepublic 35–40(516) 23(3061) 30(828) 26(2510) Ecuador 10–13(2582) 18–20(2736) 14–18(457) 42–48(890) ElSalvador 4(1306) 18–32(2498) 14–15(421) 46–50(1007) Guatemala 67–70(1729) 24(4921) 68–75(1456) 52–53(3001) Honduras 21–32(524) 30–32(1273) 44–54(449) 58–67(871) Nicaragua 19(508) 0–0.5(1081) 65(312) 0.3(383) Panama 4–8(2522) 8(3040) 23–37(1263) 26–39(1749) Paraguay 6–15(1119) 16(694) 37–55(1055) 57–59(721) Peru 43–56(463/282) 32(1401/1766) 68–71(185/169) 66(583) Venezuela 4–10(11316) 13–14(1450) 38–39(2666)a 60(377) a Klebsiellaspp.
70
60
50
P
ercentage of resitant isolates
40 30 18 41 44 55 20 NR 58 69 20 31 20 9 16 28 30 38 9 15 33 10 0 Colombia Dominican Republic Ecuador E. coli K. pneumoniae
El Salvador Guatemala Honduras Panama Paraguay Peru
Fig.4–FindingsofthePan-AmericanHealthOrganization(PAHO)summarizingthefrequencyofnosocomialEscherichiacoli
andKlebsiellapneumoniaeisolatesresistanttocefepimein2009.35NR,notreported.
Klebsiellaspp.exhibitedunacceptablylowsusceptibilityrates
tocephalosporinsinallfourcountries(40–67%).The
suscep-tibilitiesofE.coliandKlebsiellaspp.weremodestlyhigherto
cefepimethantothird-generationcephalosporins.33
InagreementwithSENTRY,aconsolidated2009network
analysis involving 14 hospitals in Chile revealed that 78%
and79%ofE.colibloodandurinecultures,respectively,were
susceptibletocefotaxime.55 Remarkablesusceptibilityrates
were observedforcarbapenems(≥99.9%)while
susceptibil-ityrateswere≥90%forpiperacillin/tazobactamandamikacin
andlowerforciprofloxacin(61–64%).55
Surveillancewasconductedin2006–2008bytheColombian
NosocomialResistanceStudyGroup,consistingof14
tertiary-carehospitalsinsevenmajorcities.56AmongE.coliisolates
fromgeneralwards(N>2300eachyear)andadultICUs(N>550
eachyear),resistancetothird-generationcephalosporinswas
lowandstableatratesrangingfrom2%to8%.Among
iso-latesfromadultICUs,resistancetocefepimewasalsostable
at4–5%duringthisperiod.ForK.pneumoniae,resistancerates
tothird-generationcephalosporins(ceftazidimeand
ceftria-xone)amongisolatesfromgeneralwardswere19–20%in2006
(N=948);24–29%in2007(N=1244),and15%in2008(N=1038).
AmongK.pneumoniaeisolatesfromadultICUs,resistanceto
third-generationcephalosporinswas24–25%in2006(N=497),
20–31%in2007(N=800),and9–24%in2008(N=602).Among
isolatesfromadultICUs,resistancetocefepimewas12%in
2006,18%in2007,and11%in2008.56
In the independent cohort studies that reported
quan-titative susceptibility data on Enterobacteriaceae harboring
ESBLs,co-resistancetomultiplecommonlyusedantimicrobial
agentsbesidesresistancetothird-generationcephalosporins
wasevident.37–39,52Moderate tohigh resistancerates(>15%
to<81%)were observedforaminoglycosides,trimethoprim/
sulfamethoxazole, piperacillin/tazobactam,and quinolones,
whereas lowresistancerates(<10%)were observedfor
car-bapenemsandtigecycline.37–41,52
Risk
factors
Studies conductedin locations throughoutthe worldhave
identified multiple risk factors for infection with
ESBL-producing Enterobacteriaceae inhospitalizedpatients.57–61 In
multivariate analyses in these studies, the following risk
factors were identified: previous antibioticuse (specifically,
quinolones,59 cephalosporins,57 oxyimino-cephalosporins,58
piperacillin/tazobactam,57 or -lactams with an oxyimino
group60), recurrent infections,59 hemodialysis,61 urinary
catheterization,58 artificial nutrition,59 and residence in a
nursinghome.61
There arefew studiesofriskfactors forESBL-producing
EnterobacteriaceaeinLatinAmerica.Potentialriskfactorsfor
theoccurrenceofinvasiveinfectionsarisingfromESBL-and
non-ESBL-producingE.coliandKlebsiellaspp.wereassessedin
aninternational,prospective,observationalstudyconducted
by the SENTRY Antimicrobial Surveillance Program, which
included 11 Latin American hospitals, from 2001–2002.62
Althoughunderlyingcomorbiditiesandpotentialriskfactors
weregenerallysimilarbetweenESBLandnon-ESBLcases,a
higherproportionofESBLcaseshadagastrostomyor
jejunos-tomy tube (30.3% vs. 6.7%, p=0.008), required ventilation
assistance(64.8%vs.38.2%,p=0.005),orhadbeenadmitted
toICU (65.6%vs. 41.0%,p=0.006)comparedwithnon-ESBL
cases.62
Amongsingle-centerstudies,multivariateanalysisof
all episodes of K. pneumoniae bacteremia for the period
1993–2002 in a Mexican referral center revealed prior use
of cephalosporins (Odds ratio [OR] 7.6, 95% CI 1.1–53.5;
p=0.039) and admission to ICU (OR 5.6, 95% CI 1.1–27.9;
p=0.033)assignificantriskfactors.63Useofbroad-spectrum
cephalosporins alsofeatured as the onlyindependent
pre-dictor of ESBL-producing enterobacteriaceae strains (n=90)
causingbacteremiainarecentlypublishedMexicanstudy,64
and use of third-generation cephalosporins (p=0.008) was
a risk factor for colonization of ESBL-producing strains of
KlebsiellasppinapediatricICUinBrazilin2008.65 Another
LatinAmerican study found arelationshipbetween use of
ciprofloxacinandprevalenceofESBL-producingK.pneumoniae
inahospitalsetting.66
Discussion
Since the first cases and outbreaks of infections by
ESBL-producingEnterobacteriaceaewerereportedinLatinAmerican
hospitals, there has been a steady increase in the overall
prevalenceand in the number of typesof ESBLs detected.
Accordingtoregion-widesurveillancedata(ie,SENTRY,TEST,
SMART, PAHO, and API) and findings from independent
country-specificcohortstudies,ESBLproductionamong
Kleb-siellaspp.canbeconsideredendemicinLatinAmerica.The
balanceofdataindicatesthatratesofnosocomialinfection
caused byESBL-producing Enterobacteriaceae, particularly K.
pneumoniae,arehighinLatinAmericacomparedwithother
worldregions(Fig.1).Morespecifically,therehasbeenarapid
spreadofCTX-Menzymes throughoutLatinAmerican
hos-pitals,which has been facilitated byhorizontal transferof
encodingplasmidsandsuccessfulclones.Whileweobserved
ageographicaltrendintheprevalenceofafinitenumberof
CTX-MenzymesubtypesinLatinAmerica(i.e CTX-M-15in
theNorth;CTX-M-2intheSouth),therewasclearevidence
thatthisregionalassociationisweakeningasCTX-Msbecome
evenmorewidespreadandevolvelocally.
In surveillance data reviewed for this article (Table 3),
45–53%ofK.pneumoniaeisolatesarenonsusceptibleto
third-generationcephalosporins,comparedwith21–27%resistance
associatedwithK.pneumoniaeHAIsintheUnitedStates.67The
northerncountriesofGuatemala,Honduras,andMexicohave
highratesofcephalosporin-resistantE.coli,whileArgentina,
Brazil, Colombia, and Panama have lower rates. For
Kleb-siellaspp.,Argentina,Brazil,Chile,Guatemala,andHonduras
are experiencing especially high rates of
cephalosporin-resistant strains, while Colombia, Panama, and Venezuela
havelowerrates.Independentcohortdatashowedthatitis
notuncommoninLatinAmericatoencounterESBL-producing
Enterobacteriaceaethatarenonsusceptibletocefepime,exhibit
high rates of resistance to fluoroquinolones and
ampi-cillin/sulbactam,andhaveappreciableratesofresistanceto
aminoglycosidesand piperacillin/tazobactam.Susceptibility
ofESBL-producingEnterobacteriaceaetothecarbapenems,
tige-cycline,andcolistinremainsmuchhigher(>90%).
There are many possibleexplanations forthe observed
differences between countries and regions. Reported
sus-ceptibility rates may have differed because of selection
of centers (public versus private) or other biases in study
design,smallnumbersofisolatescollectedinsomesettings,
differing laboratory methods, or quality control in some
laboratories.Reportedresistanceratesmay alsoreflectreal
differencesinprevalenceofresistantpathogensarisingfrom
local outbreaks, differences in antimicrobial prescribing
practices (including use of cephalosporins), differences in
facilities (e.g., rooms with multiple beds or overcrowded
conditions),andlocalinfectioncontrolmeasures(orthelack
thereof). Unfortunatelythereare nostudies that
systemat-ically investigate these differences between countries and
facilities in Latin America and their effect on prevalence
of ESBL-producing pathogens. Surveillance data must also
be read carefully because some sources report resistance
rates, whileothersreport susceptibilityrates—and because
nonsusceptibilityisnotthesameasresistance.Furthermore,
data may over-represent tertiary care hospitalswith more
complicated patient populations receiving more intensive
carethanthegeneralhospitalpopulation.
The expanding geographic spread of ESBL-producing
Enterobacteriaceae in the community and hospital setting
underscores the importance of clinical and microbiologic
recognitionoftheseenzymesatmultiplelevelsofhealthcare.
SurveillancedatacollectedregionallyinLatinAmerica may
beusedtoguideempirictreatmentofpatientssuspectedof
multidrug-resistantinfection,basedontheirindividualrisk
level.Forexample,ithasbeenshownthatpatientswithage65
yearsorolder,recentuseofantibiotics,recenthospitalization
orstayinlong-termcarefacility,andmalesexhaveagreater
likelihoodofinfectionbyESBL-producingEnterobacteriaceae;24
suchpatients maybesuspected ofinfectionwithresistant
pathogens and treated accordingly. However,knowledgeof
regionalsurveillancedataandpatientrisklevel isnot
ade-quatetoguideoptimalchoiceoftherapy.Physiciansshould
beawareoflocaldataregardingtheprevalenceand
antimicro-bialsusceptibilitiesofESBL-producingbacterialstrainsintheir
particularcityandhospital,informationthatcanhelpguide
treatmentchoicesforpatientsinaparticularfacility.When
possible, pathogen identification (at the genusand species
level)andinformationabouttheinvitroantimicrobial
resis-tanceprofileofthepathogeninfectingtheindividualpatient
canguidethechoiceandadjustmentofantimicrobials
dur-ingthecourseoftreatment.68Prospectiveobservationaldata
have shownthat patients havea survivaladvantagewhen
the correctantimicrobialagentis chosenasinitialtherapy
ratherthanempiricagentsthatprovidenocoverageagainst
theresponsiblepathogen.69
Collaborative institutional, local, national, and regional
surveillanceofESBL-producingEnterobacteriaceaeisrequired
toassist diagnosis,supporttreatmentdecisions, and guide
antimicrobial stewardship and infection control efforts.68
The US Clinical and Laboratory Standards Institute (CLSI)
and the UK Health Protection Agency (HPA) have
pub-lished guidelines for the detection of ESBL-producing
organisms.70 Following PAHO surveillance system
recom-mendations, CLSI guidelines are followed in most Latin
AmericancountriestodetectthepresenceofESBL-mediated
resistance. The difficulty in detecting and classifying
spe-cific ESBLs in the local setting is demonstrated by the
fact thathundreds ofdifferent ESBLshavebeen described,
alone(http://www.lahey.org/studies/other.asp).Morethan890
uniqueproteinsequencesfor-lactamasesweredetermined
bylate2009.16However,findingsfromLatinAmerican
stud-ies show that molecular biology techniques can be useful
incharacterizingvirulentK.pneumoniaeclonesisolatedfrom
patients and healthcare workers.21,71,72 Thetechnology to
identifygenesconferringresistanceisimprovingquicklyand
isbecomingmoreautomated.Ideally,surveillanceprograms
incitiesandhospitalsshouldprovidereal-timeinformation
about phenotype and mechanism of resistancein a rapid,
accurate,andreproduciblemanner.
Antimicrobial stewardship in conjunction with local
surveillance is also required to preserve the antimicrobial
integrity of a limited arsenal of agents. More research is
required to elucidate the risk factors for acquiring
ESBL-producing Enterobacteriaceae, althoughit can bestated that
antimicrobialtreatmentistheprimarycause.Encouragingly,
a 2002–2006 study in Colombia showed that restriction of
third-generationcephalosporinscanresultinsignificant
(5-fold)reductioninthenumber ofESBL-producing isolates.73
However,treatment withcefepimeis notrecommended in
areas wherethereis ahigh prevalenceofcirculating
CTX-Mssinceclinicalfailures oftenresultinpatientswithhigh
inoculuminfections.72Carbapenemsareatreatmentofchoice
forinfectionscausedbyESBL-producingEnterobacteriaceae,but
anundesirable consequenceof their use may be selection
ofcarbapenem-resistantnon-fermenterGram-negativebacilli
andEnterobacteriaceae.72,74–76 Instructionsonhow torestrict
andcyclecertainantimicrobialagentsforspecificindications,
framedwithinareal-timesurveillance-baseddrugformulary,
offerthebestconditionsforrationaldruguse.
Patient-to-patient transmission of ESBL-producing
pathogenshasbeenreported;thisislikelyamoreimportant
mode ofinfection withK. pneumoniaethan withE. coli.77,78
However,this issuehasnot beenstudied inLatinAmerica
beyond nosocomial outbreaks. Because of difficulties with
infectioncontrol,patient-to-patienttransmissioncouldplay
animportantroleinLatinAmericanhealthcareinstitutions.
Therefore,infectioncontroleffortsarecrucialinreducingthe
prevalenceof drug-resistant pathogens.Local outbreaks of
ESBL-producingKlebsiellaspp.strainshavebeensuccessfully
addressed in Latin American settings through standard
infectioncontrolpractices,includingdisinfectionoftheunit,
re-enforcinghandhygieneandbarriercontrolmeasures,and
adjustingantimicrobialprescribingpractices.21,72,79
Insummary,theproblemofhighinfectionratesby
ESBL-producing Enterobacteriaceae in hospitals of Latin America
isexacerbatedbythespreadofmultidrug-resistantstrains.
Antimicrobialsurveillanceattheunit,hospital,city,national,
andregionallevelisrecommendedtoguidedecisionmaking
aboutinfectioncontroleffortsandappropriateantimicrobial
treatment.
Conflicts
of
interest
ManuelGuzmánBlancoisorhasbeenamemberofadvisory
boardsofMerck,Pfizer,BectonandDickinson.Hehasreceived
researchfundsfromPfizer,Merck,GlaxoandNovartis.JaimeA.
LabarcahasbeenamemberofadvisoryboardsofMerckSharp
&DhomeandPfizer,hasreceivedresearchfundsfromMerck
Sharp&Dhome,andhasparticipatedinclinicalstudiesfor
SanofiPasteur.MariaVirginiaVillegashasbeenamemberof
advisoryboardsofMerckandPfizerandhasreceivedresearch
fundsfromPfizer, Merck,Novartis,AstraZeneca,MerckS.A,
Bayer,JanssenCilagandBiomeriux.EduardoGotuzzohasbeen
aconsultanttoPfizerandhasreceivedresearchfundsfrom
Johnson&Johnson.
Acknowledgements
ThispublicationwasfundedbyPfizerInc.Medicalwriting
sup-portwasprovidedbyMalcolmDarkesandLisaBakerofEngage
ScientificSolutionsandwasfundedbyPfizerInc.
Appendix
A.
LatinAmericaWorkingGrouponBacterialResistance:
Carlos Alvarez (Hospital Universitario San Ignacio and
Pontificia Universidad Javeriana, Bogotá, Colombia), Luis
Bavestrello(ClinicaRe ˜naca,Vi ˜naDelMar,Chile),EitanBerezin
(SantaCasadeSãoPauloSchoolofMedicine,Brazil),Eduardo
Gotuzzo(UniversidadPeruanaCayetanoHeredia,Lima,Peru),
ManuelGuzmán-Blanco(HospitalPrivadoCentroMédicode
Caracas,Venezuela),JaimeA.Labarca(PontificiaUniversidad
Católica de Chile, Santiago, Chile), Carlos M. Luna
(Hospi-tal deClínicas Joséde SanMartinHospital, Universidadde
Buenos Aires, Argentina), Carlos Mejía (Hospital Roosevelt,
GuatemalaCity,Guatemala),SimoneNouer(Hospital
Univer-sitárioClementinoFragaFilho,RiodeJaneiro,Brazil),Eduardo
Rodríguez-Noriega(HospitalCivildeGuadalajaraFrayAntonio
Alcalde,Guadalajara,Mexico),MauroJoséCostaSalles
(Hospi-tal Irmandadeda SantaCasade Misericórdiade SãoPaulo,
Brazil),CarlosSeas(UniversidadPeruanaCayetanoHeredia,
Lima,Peru),FortinoSolórzanoSantos(HospitaldePediatría
CentroMédicoNacionalSigloXXI,MexicoCity,Mexico),Maria
Virginia Villegas(International CenterforMedicalResearch
andTraining[CIDEIM],Cali,Colombia),JeanneteZurita
(Hospi-talVozandesandPontificiaUniversidadCatólicadelEcuador,
Quito,Ecuador).
r
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f
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n
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e
s
1.WorldHealthOrganization.Reportontheburdenofendemic
healthcare-associatedinfectionworldwide;2011.Availableat
http://whqlibdoc.who.int/publications/2011/9789241501507 eng.pdf[accessed20.12.11].
2.EuropeanCentreforDiseasePreventionandControl.Annual
epidemiologicalreportReportingon2009surveillancedata
and2010epidemicintelligencedata;2011.Availableathttp://
www.ecdc.europa.eu/en/publications/Publications/Forms/ ECDCDispForm.aspx?ID=767[accessed17.07.12].
3.AllegranziB,BagheriNejadS,CombescureC,etal.Burdenof endemichealth-care-associatedinfectionindeveloping countries:systematicreviewandmeta-analysis.Lancet. 2011;377:228–41.
4.VincentJL,RelloJ,MarshallJ,etal.Internationalstudyofthe prevalenceandoutcomesofinfectioninintensivecareunits. JAMA.2009;302:2323–9.
5. FalagasME,BliziotisIA.Pandrug-resistantGram-negative bacteria:thedawnofthepost-antibioticera?IntJAntimicrob Agents.2007;29:630–6.
6. SavardP,PerlTM.Acallforaction:managingtheemergence ofmultidrug-resistantEnterobacteriaceaeintheacutecare settings.CurrOpinInfectDis.2012;25:371–7.
7. KelesidisT,KarageorgopoulosDE,KelesidisI,FalagasME. Tigecyclineforthetreatmentofmultidrug-resistant
Enterobacteriaceae:asystematicreviewoftheevidencefrom microbiologicalandclinicalstudies.JAntimicrobChemother. 2008;62:895–904.
8. MendesRE,RhombergPR,BellJM,TurnidgeJD,SaderHS. Doripenemactivitytestedagainstaglobalcollectionof Enterobacteriaceae,includingisolatesresistanttoother extended-spectrumagents.DiagnMicrobiolInfectDis. 2009;63:415–25.
9. BiedenbachDJ,MoetGJ,JonesRN.Occurrenceand antimicrobialresistancepatterncomparisonsamong bloodstreaminfectionisolatesfromtheSENTRY AntimicrobialSurveillanceProgram(1997–2002).Diagn MicrobiolInfectDis.2004;50:59–69.
10.AndradeSS,SaderHS,JonesRN,PereiraAS,PignatariAC, GalesAC.Increasedresistancetofirst-lineagentsamong bacterialpathogensisolatedfromurinarytractinfectionsin LatinAmerica:timeforlocalguidelines?MemInstOswaldo Cruz.2006;101:741–8.
11.CasellasJM.Resultadosencuestanúmero7.RevPanam Infectol.2006;8:48–51.
12.CasellasJM.ResistenciaalosantibacterianosenAmérica Latina:consecuenciasparalainfectología.RevPanamSalud Publica.2011;30:519–28.
13.GalesAC,SaderHS,JonesRN.Urinarytractinfectiontrendsin LatinAmericanhospitals:reportfromtheSENTRY
antimicrobialsurveillanceprogram(1997–2000).Diagn MicrobiolInfectDis.2002;44:289–99.
14.Guzmán-BlancoM,CasellasJM,SaderHS.Bacterialresistance toantimicrobialagentsinLatinAmerica.Thegiantis awakening.InfectDisClinNorthAm.2000;14:67–81. 15.PatersonDL,BonomoRA.Extended-spectrum
beta-lactamases:aclinicalupdate.ClinMicrobiolRev. 2005;18:657–86.
16.BushK,JacobyGA.Updatedfunctionalclassificationof beta-lactamases.AntimicrobAgentsChemother. 2010;54:969–76.
17.CasellasJM,QuinterosMG.ALatinAmerican“pointdevue” ontheepidemiology,control,andtreatmentoptionsof infectionscausedbyextended-spectrumbeta-lactamase producers.In:Amabile-CuevasCF,editor.Antimicrobial resistanceinbacteria.Wymondham:HorizonBioscience; 2006.
18.CantonR,CoqueTM.TheCTX-Mbeta-lactamasepandemic. CurrOpinMicrobiol.2006;9:466–75.
19.CasellasJM,GoldbergM.Incidenceofstrainsproducing extendedspectrumbeta-lactamasesinArgentina.Infection. 1989;17:434–6.
20.Gonzalez-VertizA,Alcantar-CurielD,CuauhtliM,etal. Multiresistantextended-spectrumbeta-lactamase-producing
Klebsiellapneumoniaecausinganoutbreakofnosocomial bloodstreaminfection.InfectControlHospEpidemiol. 2001;22:723–5.
21.OtmanJ,CavassinED,PeruginiME,VidottoMC.Anoutbreak ofextended-spectrumbeta-lactamase-producingKlebsiella
speciesinaneonatalintensivecareunitinBrazil.Infect ControlHospEpidemiol.2002;23:8–9.
22.SaderHS,GalesAC,PfallerMA,etal.Pathogenfrequencyand resistancepatternsinBrazilianhospitals:summaryofresults fromthreeyearsoftheSENTRYAntimicrobialSurveillance Program.BrazJInfectDis.2001;5:200–14.
23.TurnerPJ.Extended-spectrumbeta-lactamases.ClinInfect Dis.2005;441Suppl.:S273–5.
24.Ben-AmiR,Rodríguez-Ba ˜noJ,ArslanH,etal.Amultinational surveyofriskfactorsforinfectionwithextended-spectrum beta-lactamase-producingEnterobacteriaceaein
nonhospitalizedpatients.ClinInfectDis.2009;49: 682–90.
25.QuinterosM,RadiceM,GardellaN,etal.Extended-spectrum beta-lactamasesinenterobacteriaceaeinBuenosAires, Argentina,publichospitals.AntimicrobAgentsChemother. 2003;47:2864–7.
26.VillegasMV,CorreaA,PerezF,etal.CTX-M-12beta-lactamase inaKlebsiellapneumoniaeclinicalisolateinColombia. AntimicrobAgentsChemother.2004;48:629–31.
27.RossiF,BaqueroF,HsuehPR,etal.Invitrosusceptibilitiesof aerobicandfacultativelyanaerobicGram-negativebacilli isolatedfrompatientswithintra-abdominalinfections worldwide:2004resultsfromSMART(StudyforMonitoring AntimicrobialResistanceTrends).JAntimicrobChemother. 2006;58:205–10.
28.BaqueroF,HsuehPR,PatersonDL,etal.Invitro susceptibilitiesofaerobicandfacultativelyanaerobic gram-negativebacilliisolatedfrompatientswith intra-abdominalinfectionsworldwide:2005resultsfrom StudyforMonitoringAntimicrobialResistanceTrends (SMART).SurgInfect(Larchmt).2009;10:99–104. 29.VillegasMV,BlancoMG,Sifuentes-OsornioJ,RossiF.
Increasingprevalenceofextended-spectrum-beta-lactamase amongGram-negativebacilliinLatinAmerica—2008update fromtheStudyforMonitoringAntimicrobialResistance Trends(SMART).BrazJInfectDis.2011;15:34–9.
30.HawserSP,BouchillonSK,HobanDJ,etal.Lowfrequencyof ertapenem-resistantintra-abdominalisolatesof
EscherichiacolifromLatinAmerica:susceptibility, ESBL-occurrence,andmolecularcharacterisation(SMART 2008–2009).JChemother.2012;24:6–11.
31.ReinertRR,LowDE,RossiF,ZhangX,WattalC,DowzickyMJ. Antimicrobialsusceptibilityamongorganismsfromthe Asia/PacificRim,EuropeandLatinandNorthAmerica collectedaspartofTESTandtheinvitroactivityof tigecycline.JAntimicrobChemother.2007;60:1018–29. 32.Fernández-CanigiaL,DowzickyMJ.Susceptibilityof
importantGram-negativepathogenstotigecyclineandother antibioticsinLatinAmericabetween2004and2010.AnnClin MicrobiolAntimicrob.2012;11:29.
33.GalesAC,CastanheiraM,JonesRN,SaderHS.Antimicrobial resistanceamongGram-negativebacilliisolatedfromLatin America:resultsfromSENTRYAntimicrobialSurveillance Program(LatinAmerica,2008–2010).DiagnMicrobiolInfect Dis.2012;73:354–60.
34.Pan-AmericanHealthOrganization.InformeAnualdelaRed
deMonitoreo/VigilanciadelaResistenciaalosAntibióticos–
2006;2006.Availableathttp://www2.paho.org/hq/
dmdocuments/2009/amr2006informeanual.pdf[accessed 06.03.13].
35.Pan-AmericanHealthOrganization.InformeAnualdelaRed
deMonitoreo/VigilanciadelaResistenciaalos
Antibióticos/2009;2009.Availableathttp://new.paho.org/hq/
index.php?option=comcontent&view=article&id=6221& Itemid=4328&lang=en[accessed06.03.13].
36.HobanDJ,NicolleLE,HawserS,BouchillonS,BadalR. Antimicrobialsusceptibilityofglobalinpatienturinarytract isolatesofEscherichiacoli:resultsfromtheStudyfor MonitoringAntimicrobialResistanceTrends(SMART) program:2009–2010.DiagnMicrobiolInfectDis. 2011;70:507–11.
37.GaitanCS,EspinalMP.Molecularcharacterizationof
andKlebsiellapneumoniaeinhospitalsoftheCaribeanRegion. ColombiaRevChilenaInfectol.2009;26:239–46.
38.Garza-GonzalezE,MendozaIbarraS.I.,Llaca-DiazJM, GonzalezGM.Molecularcharacterizationandantimicrobial susceptibilityofextended-spectrum
{beta}-lactamase-producingEnterobacteriaceaeisolatesatatertiary-carecentre inMonterrey.MexicoJMedMicrobiol.2011;60:84–90. 39.Morfin-OteroR,Mendoza-OlazaranS,Silva-SanchezJ,etal.
CharacterizationofEnterobacteriaceaeisolatesobtainedfroma tertiarycarehospitalinMexico,whichproduces
extended-spectrumbeta-lactamase.MicrobDrugResist.2013. 40.MarcanoD,DeJesúsA,HernándezL,TorresL.Frequencyof
enzymesassociatedwithreducedsensitivitytobeta-lactam antibioticsinenterobacteriaisolates,Caracas,Venezuela.Rev PanamSaludPublica.2011;30:529–34.
41.daSilvaDiasRC,Borges-NetoAA,D’AlmeidaFerraiuoliGI, de-OliveiraMP,RileyLW,MoreiraBM.PrevalenceofAmpCand otherbeta-lactamasesinenterobacteriaatalargeurban universityhospitalinBrazil.DiagnMicrobiolInfectDis. 2008;60:79–87.
42.Navarro-NavarroM,Robles-ZepedaRE,Garibay-EscobarA, Ruiz-BustosE.Hospitalandcommunity-acquired beta-lactamases-producingEscherichiacoliandKlebsiella pneumoniaeathospitalsinHermosillo.SonoraSaludPublica Mex.2011;53:341–4.
43.TedescoMaiullariRM,GuevaraA.Enterobacteriaproducersof extended-spectrumbeta-lactamaseinahospitalfrom Venezuela.InfezMed.2012;20:93–9.
44.Qui ˜nonesD,ValverdeA,Rodriguez-BanosM,etal.Highclonal diversityinanon-outbreaksituationofclinical ESBL-producingKlebsiellapneumoniaeisolatesintheFirstNational SurveillancePrograminCuba.MicrobDrugResist.2013. 45.WollheimC,GuerraIM,ConteVD,etal.Nosocomialand communityinfectionsduetoclassAextended-spectrum beta-lactamase(ESBLA)-producingEscherichiacoliand
Klebsiellaspp.insouthernBrazil.BrazJInfectDis. 2011;15:138–43.
46.NogueiraKdaS,HigutiIH,doNascimentoAJ,etal. Occurrenceofextended-spectrumbeta-lactamasesin
Enterobacteriaceaeisolatedfromhospitalizedpatientsin Curitiba,southernBrazil.BrazJInfectDis.2006;10:390–5. 47.MenaP,GonzálezAJC,JosefinaM.Extendedspectrum
beta-lactamasedetectioninEnterobacteriaceaefamily strains.Kasmera.2009;37:25–37.
48.SennatiS,SantellaG,DiConzaJ,etal.Changing epidemiologyofextended-spectrumbeta-lactamasesin Argentina:emergenceofCTX-M-15.AntimicrobAgents Chemother.2012;56:6003–5.
49.CelenzaG,PellegriniC,CaccamoM,SegatoreB,Amicosante G,PerilliM.Spreadofbla(CTX-M-type)andbla(PER-2) beta-lactamasegenesinclinicalisolatesfromBolivian hospitals.JAntimicrobChemother.2006;57:
975–8.
50.PoirelL,NaasT,LeThomasI,KarimA,BingenE,NordmannP. CTX-M-typeextended-spectrumbeta-lactamasethat hydrolyzesceftazidimethroughasingleaminoacid substitutionintheomegaloop.AntimicrobAgents Chemother.2001;45:3355–61.
51.DropaM,BalsalobreLC,LincopanN,etal.Extended-spectrum beta-lactamasesamongEnterobacteriaceaeisolatedinapublic hospitalinBrazil.RevInstMedTropSaoPaulo.2009;51:203–9. 52.PulidoIY,MantillaJR,ValenzuelaEM,RegueroMT,Gonzalez
EB.Distributionofextendedspectrum
beta-lactamases-codifyinggenesinKlebsiellapneumoniae isolatesfromhospitalsofBogota,DC,Colombia.Biomedica. 2011;31:15–20.
53.BelloH,TrabalN,IbanezD,etal.Beta-lactamasesotherthan TEMandSHVamongstrainsofKlebsiellapneumoniaesubsp
pneumoniaeisolatedfromChileanhospitals.RevMedChil. 2005;133:737–9.
54.CasellasJM.Resultadosdela7aEncuestadelComitéde ResistenciaaAntimicrobianosdelaAsociación
PanamericanadeInfectología.RevPanamInfectol.2006;8: 48–55.
55.SilvaFO,CifuentesM,PintoEC;representingtheCollaborative GrouponAntimicrobialResistance.Resultsofantimicrobial susceptibilitysurveillanceinChile:consolidatinganetwork. RevChileInfect.2011;28:19–27.
56.Brice ˜noDF,CorreaA,ValenciaC,etal.Antimicrobial resistanceofGramnegativebacilliisolatedfromtertiary-care hospitalsinColombia.Biomedica.2010;30:371–81.
57.Cohen-NahumK,Saidel-OdesL,RiesenbergK,SchlaefferF, BorerA.Urinarytractinfectionscausedbymulti-drug resistantProteusmirabilis:riskfactorsandclinicaloutcomes. Infection.2010;38:41–6.
58.WuUI,YangCS,ChenWC,ChenYC,ChangSC.Riskfactors forbloodstreaminfectionsduetoextended-spectrum beta-lactamase-producingEscherichiacoli.JMicrobiol ImmunolInfect.2010;43:310–6.
59.CassierP,LallechereS,AhoS,etal.Cephalosporinand fluoroquinolonecombinationsarehighlyassociatedwith CTX-Mbeta-lactamase-producingEscherichiacoli:a case–controlstudyinaFrenchteachinghospital.Clin MicrobiolInfect.2011;17:1746–51.
60.PatersonDL,KoWC,VonGottbergA,etal.International prospectivestudyofKlebsiellapneumoniaebacteremia: implicationsofextended-spectrumbeta-lactamase productioninnosocomialInfections.AnnInternMed. 2004;140:26–32.
61.SaelyS,KayeKS,FairfaxMR,ChopraT,PogueJM. Investigatingtheimpactofthedefinitionofprevious antibioticexposurerelatedtoisolationofextendedspectrum beta-lactamase-producingKlebsiellapneumoniae.AmJInfect Control.2011;39:390–5.
62.BhavnaniSM,AmbrosePG,CraigWA,DudleyMN,JonesRN. OutcomesevaluationofpatientswithESBL-and
non-ESBL-producingEscherichiacoliandKlebsiellaspeciesas definedbyCLSIreferencemethods:reportfromtheSENTRY AntimicrobialSurveillanceProgram.DiagnMicrobiolInfect Dis.2006;54:231–6.
63.Mosqueda-GómezJL,Monta ˜no-LozaA,RolónAL,etal. Molecularepidemiologyandriskfactorsofbloodstream infectionscausedbyextended-spectrum
beta-lactamase-producingKlebsiellapneumoniaeA case–controlstudy.IntJInfectDis.2008;12: 653–9.
64.MuroS,Garza-GonzalezE,Camacho-OrtizA,etal.Risk factorsassociatedwithextended-spectrum
beta-lactamase-producingEnterobacteriaceaenosocomial bloodstreaminfectionsinatertiarycarehospital:aclinical andmolecularanalysis.Chemotherapy.2012;58:
217–24.
65.LevySS,MelloMJ,Gusmao-FilhoFA,CorreiaJB.Colonisation byextended-spectrumbeta-lactamase-producingKlebsiella
spp.inapaediatricintensivecareunit.JHospInfect. 2010;76:66–9.
66.BermejoJ,BencomoB,ArnesiN,LesnaberesP,BordaN, NotarioR.Highrelationshipbetweenciprofloxacinuseand prevalenceofESBLKlebsiellapneumoniae.RevChilenaInfectol. 2006;23:316–20.
67.HidronAI,EdwardsJR,PatelJ,etal.NHSNannualupdate: antimicrobial-resistantpathogensassociatedwith healthcare-associatedinfections:annualsummaryofdata reportedtotheNationalHealthcareSafetyNetworkatthe CentersforDiseaseControlandPrevention,2006–2007.Infect ControlHospEpidemiol.2008;29:996–1011.
68.O’BrienTF,StellingJ.Integratedmultilevelsurveillanceofthe world’sinfectingmicrobesandtheirresistanceto
antimicrobialagents.ClinMicrobiolRev.2011;24:281–95. 69.Alvarez-LermaF.Modificationofempiricantibiotictreatment
inpatientswithpneumoniaacquiredintheintensivecare unit.ICU-AcquiredPneumoniaStudyGroup.IntensiveCare Med.1996;22:387–94.
70.PitoutJD,LauplandKB.Extended-spectrum
beta-lactamase-producingEnterobacteriaceae:anemerging public-healthconcern.LancetInfectDis.2008;8:159–66. 71.AndradeV,SilvaJ.CharacterizationofSHV-5
beta-lactamase-producingKlebsiellapneumoniaeinan intensivecareunit.SaludPublicaMex.2004;46:524–8. 72.CasellasJM,NanniniE,RadiceM,etal.Estudiodeunbrote
debidoaaisladosdeKlebsiellapneumoniaeproductoresde betalactamasasdeespectroextendidoenuncentro asistencialdeRosario-Argentina.RevPanamInfectol. 2005;7:21–7.
73.GalvisCE,Mari ˜noaAC,MonroyJ,PossoYH.Theimpactofan antibioticrestrictionpolicyintheintensivecareunitatthe hospitalmilitarcentral.RevMed.2008:2008.
74.FurtadoGH,PerdizLB,OnitaJH,WeySB,MedeirosEA. Correlationbetweenratesofcarbapenemconsumptionand
theprevalenceofcarbapenem-resistantPseudomonas aeruginosainatertiarycarehospitalinBrazil:a4-yearstudy. InfectControlHospEpidemiol.2010;31:664–6.
75.ZilberbergMD,ChenJ,ModySH,RamseyAM,ShorrAF. ImipenemresistanceofPseudomonasinpneumonia:a systematicliteraturereview.BMCPulmMed.2010;10:45. 76.Papadimitriou-OlivgerisM,MarangosM,FligouF,etal.Risk
factorsforKPC-producingKlebsiellapneumoniaeenteric colonizationuponICUadmission.JAntimicrobChemother. 2012;67:2976–81.
77.HarrisAD,KotetishviliM,ShurlandS,etal.Howimportantis patient-to-patienttransmissioninextended-spectrum beta-lactamaseEscherichiacoliacquisition.AmJInfect Control.2007;35:97–101.
78.HarrisAD,PerencevichEN,JohnsonJK,etal. Patient-to-patienttransmissionisimportantin extended-spectrumbeta-lactamase-producingKlebsiella pneumoniaeacquisition.ClinInfectDis.2007;45: 1347–50.
79.GonzálezACR,GilFG,SolórzanoMR,etal.Outbreakof multiresistantandextendedspectrum-lactamase producingKlebsiellapneumoniaeinahighriskneonatalunit. RevChilInfectol.2011;28:28–34.
