Volumen 66, Broj 4 VOJNOSANITETSKI PREGLED Strana 307Correspondence to: Radmila M. Velikovi-Radovanovi, Clinical Centre Ni, Department of Clinical Pharmacology, Zorana inia48, 18 000 Ni, Serbia. Phone +381 18 53 39 57. E-mail: farmakoterapija@yahoo.comO R I G I N A L A R T I C L E UDC 573.4021.484::615.33Correlation between antibiotic consumption and bacterial resistanceas quality indicator of proper use of these drugs in inpatientsKorelacija potronje antibiotika i bakterijske rezistencije kao indikator njihovepravilne upotrebe kod hospitalizovanih bolesnikaRadmila Velikovi-Radovanovi*, Jasmina Petrovi*, Branislava Koci,Sneana Anti, Gordana RaneloviClinical Center Ni, *Department of Clinical Pharmacology, Medical Faculty,Institute of Public Health, Ni, SerbiaAbstractBackground/Aim.Antibioticsarethemostfrequentlyused medicationsinSerbianhospitalizedpatients.Informa-tionaboutantibioticutilizationandsensitivityamonginpa-tients in Serbia is scanty, and there are no available publica-tions on the topic. The aim of this study was to investigatethecorrelationbetweenantibioticuseandbacterialresis-tance in the Clinical Center Ni, one of the biggest hospitalsinSerbia.Methods.Thedataonantibioticsuseininpa-tientswereobtainedfromthedatabaseoftheDepartmentofPharmacotherapyandexpressedasdefineddailydosesper100bed-days(DBD),during20032007.Bacterialre-sistances were given as percentages of resistant isolates. Re-sults.Duringtheinvestigationperiod,theoverallcon-sumptionofantibioticshadasignificantdecreasein2007,by22.99%(62.23:47.92DBD;p < 0.05).Themostfre-quentlyusedantibioticswerecephalosporins,followedbypenicillins,aminoglycosidesandquinolones.Hospitalami-noglycosidesconsumptionwasreducedin2007to59.9%(13.4:5.53DBD)whiletheresistancetoamikacinwasre-ducedfrom40.88%to32.1%.However,utilizationofcip-rofloxacinhadasignificantincreasein2007(120.7%).There was an alarming increase in the level of resistance tociprofloxacin inourhospital (from13.5%to28.3%inEs-cherichia coli and from 11.1 to 30.09% in Proteus mirabilis). Re-ductionofEcoliresistanttoamoxicillin+clavulanicacidcorrelatedsignificantlywiththeirutilization,whilethere-sistanceforallisolatesdecreasedfrom52.16%to24.40%.Conclusions. These results confirm an association betweenthe use of antibiotics and the prevalence of resistance. Thismethodologycouldprovidegoodqualityindicatorsofra-tional drug use and serve for local monitoring of antibioticsuse and resistance, as well as for external comparison.Key words:anti-bacterial agents; drug utilization; drug resistance,bacterial; therapeutics; quality control.ApstraktAntibiotici su najei meu svim lekovima koji se primenjujuzaleenjehospitalizovanihbolesnikauSrbiji.Podaciokori-enju i osetljivosti na antibiotike kod tih bolesnika oskudni su inema dostupnih radova o tome u naoj zemlji. Cilj ove studijebio je utvrivanje korelacije izmeu upotrebe antibiotika i ba-kterijskerezistencijekodbolesnikahospitalizovanihuKlini-kom centru Ni (KCN)uperioduod20032007. Metode.Praenje i analiza upotrebe antibiotika obavljena je u Slubi zafarmakoterapijuKCN.KorienjemAnatomicalTherapeuticChemical/DefinedDailyDosemetodologijeukupnapotronjaantibiotikaizraavanajebrojemdefinisanihdnevnihdozana100 bolesnikih dana (DBD). Ispitivanje i praenje osetljivostibakterija vreno je u Institutu za zatitu zdravlja u Niu. Bakte-rijskarezistencijaizraavanajeprocentomrezistentnihsojevabakterija.Rezultati.Utokupetogodinjegperiodapraenja,ukupna upotreba antibiotika redukovana je za 22,99% (62,23 u2003 : 47,92 DBD u 2007; p < 0,05). Najee propisivani an-tibioticibilisucefalosporini,aminoglikozidi,peniciliniihino-loni.Upotrebaaminoglikozidasmanjenajeza59,9%,dokjebakterijskarezistencijasmanjenasa40,1%na32,1%.Utvre-nojeznaajnopoveanjeupotrebeciprofloksacinau2007.uodnosu na 2004 (120,7%), to je dovelo do signifikantnog po-rasta rezistencije (Escherichia coliod11,1% do30,09% i Proteusmirabilis od 15,63% do 28,3%). Nasuprot tome, utvreno je dasnienje rezistencije E.coli signifikantno korelira sa potronjomkoamoksiklava,kojajesnienasa5,09DBDna1,19DBD(ukupnarezistencijasvihizolatasnienajesa52,16%na24,40%).Zakljuak.Potvrenajepovezanostizmeuupot-rebeantibiotikaiprevalencijebakterijskerezistencije.Prime-njena metodologija moe posluiti za praenje pravilnog kori-enjaantibiotikairezistencijenanjih,kakoulokalnimokvi-rima, tako i za komparaciju sa drugim centrima.Kljune rei:antibiotici; lekovi, korienje; lekovi, rezistencijabakterija; leenje; kvalitet, kontrola.Strana 308 VOJNOSANITETSKI PREGLED Volumen 66, Broj4Velikovi-Radovanovi R, et al. Vojnosanit Pregl 2009; 66(4): 307312.IntroductionAntibiotics are the most frequently used medications inhospitalized patients (1530% of all prescribed drugs). It hasbeenestimatedthat3050%ofhospitalizedpatientsreceiveantimicrobialagents,andthatupto50%ofprescribedanti-microbial agents are not prescribed optimally 13. It has beenshown that inappropriate antibiotic use significantly contrib-utes to increasing rates of resistant pathogens 4, 5. Bacteral re-sistanceisnowbeingrecognizedasamajorfactordeter-miningmorbidity,mortalityandcostsinthehospital.Ithasbeen generally recognized that the prevalence of bacterial re-sistanceamongbacteriaisanunavoidableconsequenceofantibioticsuseandthatitcorrelateswiththeoveralluseofantimicrobial drugs 2, 5. Several lines of evidence suggest thatthere is a causal association between the use of antimicrobialagentsandtheprevalenceofdrugresistanceinmicroorgan-isms 68.Takingintoaccountthisescalationinbacterialre-sistanceandthelargebodyofevidenceconsideringtheoveruse of antibiotics a rational approach is a strict control ofantibioticuse.Factorsthatpromotetheemergenceofresis-tanceincludefrequentuseofbroad-spectrumantimicrobialagents, prolonged use of antimicrobial agents, more frequentuseofinvasivedevicesandprocedures 9,10.However,therearereasonsforoptimism,asstudiesinvariouscentersshowrapidreversalofresistance 7, 8.The1998EuropeanConfer-enceentitledTheMicrobialThreatemphasizedtheim-portanceofcollectingandcomparingdataofantibioticuseandbacterialresistancefromdifferentcountries 11, 12.Infor-mationaboutantibioticutilizationandsensitivityamongin-patients in Serbia is scanty, and there are no available publi-cations on the topic. The purpose of this study was to inves-tigatetheextentofantimicrobialusageandtoevaluatethebacterialresistanceintheClinicalCenterNi,oneofthebiggesthospitalsinSerbia.ThisstudygenerallyusedtheWorld Health Organization (WHO) Anatiomical TherapeuticChemical (ATC) Classification Systemand the volume unit Defined Daily Doses (DDD) 13, 14.MethodsIn this survey antibiotic consumption and bacterial sus-ceptibilityweremonitoredintheperiod2003-2007.There-sultswereanalyzedintheClinicalCenterNi,a1460-bed,3rdtertiaryhealthcareuniversityhospitalinSerbia,thatcomprisesdepartmentscoveringallmajorspecialtiesexceptforinfectiousdiseases,kidneytransplantation,hematology,oncology,surgeryandtuberculosis.Thestudyperiodex-tendedfrom2003 2007.In2003 2005,theClinicalCen-ter had 417 357, 452 993 bed-days per year.As this study did not collect any data on individual pa-tientsandsurveillancewasapartofqualityassurance,anapprovalbyEthicalCommitteewasnotconsideredneces-sary.UtilizationofantibioticsinClinicalCenterNiintheperiodfollowedwasobtainedfromthecomputerizeddata-base of the Department of Pharmacotherapy and expressed asDDD per 100 bed/days (DBD). Defined Daily Doses of anti-bacterialagentsforsystemicuselistedintheATCIndexwithDDDintheperiodfrom2003to2007wereused.Thirty-five different antibiotic drugs were used in our hospi-tal.UntilApril2005,therewasnoantibioticrestrictionpolicyinthehospitalandeveryphysiciancouldprescribeanyantibiotic,somisuseoroveruseofantibioticswascom-mon.TherehasbeenthePharmacotherapyDepartmentheresince 2005. Routine monitoring of the use of antibiotic drugsand antibacterial resistance was started in the Clinical CenterNiin2005withtheaimtopreventanincreaseinbacterialresistance and the costs of treatment. Following implementa-tionofrestrictionpolicyin2005,prescriptionofaminogly-cosides, third- and fourth-generation cephalosporins, carbap-enems, piperacillintazobactam and vancomycynwereplacedunderthecontroloftheclinicalpharmacologist.Theseagentsmayonlybeprescribedafterconsultationwiththeclinicalpharmacologistorfollowinganapprovalbythemedicaldirector.Somesurgicaldepartmentshavetheirownguidelines for surgical prophylaxis, which were developed incollaborationwithamicrobiologistandaclinicalpharma-cologist.Occasionallecturesonrationalantimicrobialdruguse are given in some departments.Thehospitalhasthreeclinicalpharmacologistssurvey-ingandanalyzingdrugutilizationandbacterialresistance,whileoneofthemisapresidentoftheDrugandTherapeu-tics Committee (DTC), within the hospital.The bacteriological laboratory of the Institute for PublicHealthNiroutinelyscreensbacterialresistance/sensitivityforallpatientsrequiringantibiotictherapyexceptforpro-phylacticuse.Bacterialstrainswereisolatedfromtheclini-calmaterialofthehospitalizedpatientsandsusceptibilitytoantibiotics was assessed by the disc diffusion method.TheprocessoftestingthesusceptibilityofbacteriatoantibacterialmedicinesandthecreationofantibiogramareconductedaccordingtorecommendationsoftheAmericanNationalCommitteeforClinicalandLaboratoryStan-dards 14, 15andaccordingtotherecommendationoftheEuropeanCommitteeforAntimicrobialSusceptibilityTest-ing(EUCAST)andtheEuropeanAssociationofClinicalMicrobiologyandInfectiousDiseases(ESCMID).Fortheinterpretationofthezonesofinhibitionthestandardswereused.Strainswereclassifiedassusceptibleorresistant(in-termediatezonesofinhibitionwereconsideredresistant).Bacterialresistancesweregivenaspercentagesofresistantisolates. The hospital specialist in infectious diseases and theclinicalpharmacologistanalyzedthedataprovidedbythemicrobiologyunitandbasedonthatcreatedahospitalpro-file.Thenumberoftheassaysperformedbythebacterio-logical laboratory was comparable for the years 2003 (2865),2004(2968),2005(3120),2006(2671)and2007(3534).The burden of resistance for each antibiotic was calculated aspercentageofallresistance+intermediateamongalltestedisolates from all patients samples (blood, urine, sputum, etc).Fortestingthesignificanceofresistancedevelopmentandchangesinantibioticsutilizationalinearanalysiswasused. The Chi-square test was used to compare antibiotic useVolumen 66, Broj 4 VOJNOSANITETSKI PREGLED Strana 309Velikovi-Radovanovi R, et al. Vojnosanit Pregl 2009; 66(4): 307312.indifferenttimeperiods.Pearson'scorrelationwasusedtodeterminetherelationshipbetweentheuseofantibioticsandthe bacterial resistance. A statistical significance was acceptedatthe5%level.TheWHONETsoftwaredevelopedbytheWHOwasutilizedfordatamanagement 16.Theantibioticre-sistance data were obtainedand presentedwith theDBDseg-ment in tables and figures. Thedatawere visualizedas adia-gram combining drug utilization (DBD) and resistance.ResultsThe consumption of antibiotics in our hospital is shownin Table 1. During the investigation period atotalconsump-tion ofantibioticshadasignificantdecrease(p < 0.01)from62.23 DBD in 2003 to 47.92 DBD in 2007.Themostfrequentlyusedantibioticswerecephalospo-rins, followed by penicillins, aminoglycosides and quinolones.In2003,ceftriaxonewasthemostfrequentlyprescribedanti-biotic and made up a quarter of the use (Figure 1).Escherichia coli was a most frequently isolated bacte-ria(15.7119.19%),followedbyStaphylococcusaureus,Staphylococcus epidermidis, Pseudomonas aeruginosa andothergram-negativebacilli.Thetypesandfrequencyofisolated bacterialstrainsper each yearofthefollowedpe-riodaredescribedinTable2.Theratesofresistanceoffrequently isolated bacteria in our hospital are presented inTable 3.Hospitalaminoglycosidesconsumptionsignificantlyreduced from 2005 (13.4 DBD) to 2007 (5.53 DBD) (59.9%;p < 0.001)(Figure1).Resistancetogentamycinandami-kacin in our study was relatively high, but it significantly de-creasedduringthemonitoredperiod.TheE.coliresistanceto amikacin reduced from 40.2% to 19.7% (Table 3).ReductionofE.coliresistanttoamoxicil-lin+clavulanic acid correlated significantly with their utili-zation(r = 0,944,p < 0.05),whiletheresistanceforallisolates was reduced from 61.58% to 46.36%. The depend-enceofthereductionofE.coliresistancetoamoxicil-lin+clavulanic on their utilization in Clinical Center Ni isshowninFigure2.Asignificantcorrelationwasfound(r =0.924; p < 0.05).Duringthesameperiod,therewasasubstantialde-creaseintheuseofceftriaxone,whiletheresistanceforallisolates was reduced from 58.2% to 48.86%.DBD0123456789ceftriaxonecefotaximebipenicillinscoamoxiclavampicilinciprofloxacingentamicin*amikacin*2003 2005 2007*Hospital aminoglycosides consumption was significantly reduced from 2003 to 2007 (p < 0.001).Fig. 1 Trends in antibiotic consumption in defined daily doses per 100 bed-days (DBD)in the Clinical Center Nifrom 2003 to 2007Table 1Antibiotic consumption in the Clinical Center Ni from 2003 to 2007DBD (%)Antibiotics2003 20052007 Ceftriaxone 8.18 (13.14) 3.60 (6.87) 6.09 (12.7) Gentamicin 7.42 (11.92) 4.21 (8.04) 3.33 (6.95) Bipenicillins 5.94 (9.55) 2.40 (4.58) 1.63 (3.40) Ciprofloxacin 2.12 (3.41) 4.68 (10.84) 5.30 (11.06) Amikacin 5.47 (8.79) 2.21 (4.22) 2.20 (4.59) Coamoxiclav 5.09 (8.18) 2.80 (5.35) 1.19 (2.48) Cefotaxime 4.94 (7.94) 1.65 (3.15) 1.28 (2.67) Cotrimoxazole 4.26 (6.85) 2.26 (4.32) 1.87 (3.96) Ampicillin 3.69 (5.93) 4.79 (9.14) 1.57 (3.28) Cefuroxime 0.96 (1.54) 3.82 (7.29) 5.97 (12.40) Other 14.16 (22.75) 18.96 (36.90) 13.76 (28.71) Total 62.23 (100) 51.38 (100) 47.92* (100)*Consumption of antibiotics had a significant decrease from 2003 to 2007 (p < 0.01)DBD defined daily doses per 100 bed-daysStrana 310 VOJNOSANITETSKI PREGLED Volumen 66, Broj4Velikovi-Radovanovi R, et al. Vojnosanit Pregl 2009; 66(4): 307312.Table 2Types and frequency of appearance of bacterial strains in the Clinical Center Nifrom 2005 to 2007Number of bacterial strains (%)Bacterials strains 200320052007 Echerichia coli 490 (15.71) 500 (18.70) 678 (19.19) Staphylococcus aureus 450 (14.42) 370 (13.85) 264 (7.47) Staphylococcus epid. 410 (13.14) 236 (8.84) 241 (6.82) Enterococcus 290 (9.29) 142 (5.32) 342 (9.68) Proteus mirabilis 210 (6.73) 154 (5.77) 177 (5.01) Pseudomonasaeuriginosa 200 (6.41) 198 (7.41) 304 (8.80)Klepsiella 160 (5.13) 118 (4.42) 201 (7.11)Eneterobacter 215 (6.78) 146 (5.46) 142 (4.08)Citrobacter 132 (4.23) 132 (4.94) 138 (3.91)Acinetobacter 120 (3.85) 83 (3.11) 106 (3.74) Other 443 (14.19) 592 (22.16) 941 (26.62) Total 3120 (100) 2671 (100) 3534 (100)Table 3Resistance of bacterial strains isolated in inpatients in the Clinical Center Ni in 2003 and 2007Resistant bacterialstrains (%)E.coli Klebsiella sp. P.aeuriginosa Eneterobacter sp. Acinetobacter sp. P.mirabilisAntibiotics 2003 2007 2003 2007 2003 2007 2003 2007 2003 2007 2003 2007Ampicillin 73.08 57.61 77.27 51.47Amoxicillin+ cla-vulanic acid52.16 24.40 80.00 73.47 83.33 81.18 79.22 78.86 42.74 28.57Cefuroxime 27.50 23.88 69.74 80.00 73.20 64.93 38.67 27.56Cefotaxime 26.46 22.42 66.67 77.62 76.19 68.21 69.57 85.71 90.48 18.99 24.19Ceftriaxone 29.14 46.08 75.59 85.46 91.50 61.21 62.71 87.84 92.80 31.34 26.32Imipenem 2.50 1.92 0 6.98 8.97 9.77 8.57 3.95 12.71 12.50 10.53Meropenem 3.70 3.7 0 1.66 15.72 11.37 0 2.7 4.41 13.22 0 5.26Gentamicin 30.34 20.10 71.13 57.14 75.97 53.49 70.23 50.64 83.12 80.30 35.04 27.68Amikacin 40.20 19.74 58.94 39.56 54.32 43.19 53.10 28.7 78.38 70.42 17.60 14.46Ciprofloxacin 15.63 28.33 40.00 69.74 44.20 58.64 40.52 52.94 75.32 77.48 11.01 30.09Number of isolates 490 678 160 201 200 304 215 142 120 106 210 177DDD defined daily dosesFig. 2 Correlation between the consumption of amoxicillin+clavulanic acidand the resistance to E. coliThere was an alarming increase in the level of resistance tociprofloxacininourhospital(from13.5%to28.3%toE.coliand from 11,1 to 30.09% to P. mirabilis). The dependence of thedevelopment of E. coli resistance to ciprofloxacin on their utili-zation in the Clinical center Ni is shown in Figure 3. A signifi-cant correlation was found (r =0.827, p = 0,025).Volumen 66, Broj 4 VOJNOSANITETSKI PREGLED Strana 311Velikovi-Radovanovi R, et al. Vojnosanit Pregl 2009; 66(4): 307312.S. aureus resistant to vancomycin and the vancomycin-resistant enterococcus were not detected.DDD defined daily dosesFig. 3 Correlation between the consumption ofciprofloxacin and the resistance to E. coliDiscussionUtilization of antibiotics in Serbia is among the highestinEurope,mostlyduetooveruseofcephalosporinesandaminoglycosides.TheEuropeanSurveillanceofAntibioticConsumption(ESAC)foundlargedifferencesinantibioticuse in inpatients. Utilization of antibiotics in the world variedgreatly, from the extremely high in Croatia and Greece, nextrate in France and to the lowest one was in the Netherland. Inthisstudywefoundhighantibioticutilizationandhighre-sistanceratesinourhospitalcomparedwithothercoun-tries 1, 11, 12, 18. A survey carried out atthreeuniversityhospi-tals,inanothercountry,showedlowertotalantibioticcon-sumption to that found at our hospital l6, 19. Unfortunately, noresistance data were included in these studies.We found high rate of resistance among the most com-monlyusedantibiotics(aminoglycosides,cephalosporines,fluoroquinolones) 20.HereitwasfoundthatresistanceofP.aeruginosatogentamicin,waschangedfrom75.9%ofre-sistant strains in 2005, to 53.5% in 2007. This means that forP.aeruginosainfectionschangeledtoimprovedsensitivity,though it is clear that gentamicin cannot be used for this kindofinfection 1, 17.Goryachkinaetal. 11showedthedecreasedresistance level for gentamicin (80% to 40%) in Russia from20032005.Atthesametime,weshowedadecreasedresistancelevel for amoxicillin+clavulanic acid (61.58 to 46.36%; samestrainsweretested).Thisprovidesanoverallimpressiononcoincidenceofresistanceandantibioticoveruse.Theresis-tanceofE.coliwasdecreasedsignificantlyfrom52.16%ofresistant strains in 2005, to 24.40% in 2007.At the beginning of this study, utilization of ciprofloxacinwaslowinourhospital(2.12DBD).TheresistanceofE.coliin inpatients was at a level of 15.5%. In the study period cipro-floxacinutilizationincreasedsignificantly(p < 0.001).Bacte-rialresistancefollowedthistrendverycloselyandreached28.3% in 2007. This is a result of the increased consumptionof ciprofloxacin from 2005 2007, the singlemost prescribeddrug.Now,theincreasedlevelsofresistancetofluoro-quinolonesamongnosocomialisolateslikeP.aeuriginosa,Serratia sppecies and Klebsiella sppecies have been reportedworldwide.The influence of hospital antibiotic policy is responsiblefor this delay. Ciprofloxacin was not placed on restricted an-tibioticslistinthesameperiodinourhospital.Fluoro-quinoloneresistancetoE.coliisemergingasasignificantprobleminhospitals.Urbaneketal. 5haveshownacorrela-tionbetweentheincreaseduseoffluoroquinolonesandtheincreaseinE.coliresistance.Resultsofnumerousstudiesshowtheimpactoffluoroquinoloneutilizationonbacterialresistance and support the need for controlled use of these ef-fectiveantibiotics 5, 19, 21.Periodsofextensiveciprofloxacinuse were associated with a significant increases in resistance.Similarly to our results, the resistance of E.colito ciproflox-acin in Spain was increased from 13.8% in 2001, to 23.4% in2005 1012. A total ciprofloxacin use was an independent pre-dictoroftheburdenofciprofloxacinresistanceinE.coliinhospitals 2123.Ourdatasupporttheconceptthatawrittenantibiotic policy which balances the use of various antibioticclasses may help to avoid disturbances of a hospitals micro-bialsensitivitypatterns 2125.Asantibacterialresistanceisamultifactorialproblem,amultisectoraleffortisneededtocontrol it. The problem of antibacterial resistance needs to beaddressed in a continuous proccess of actions. The key areasofcommunityrecommendationsforthecontrolofbacterialresistancearesurveillanceofantibioticconsumptionandre-sistancerates,optimizingantibioticuse,education,preven-tion and control 2, 3, 26, 27.ConclusionTheseresultsconfirmanassociationbetweentheprevalenceofbacterialresistanceanduseofantibiotics.Monitoringofbacterialresistancecanserveasanindicatorof quality of antibiotic use. A combined presentation of anti-biotic utilization and bacterial resistance provides clear indi-cation on both problems in relation to each other. This meth-odologyseemstobebeneficialforexternalcomparisonsaswellaslocalregulationofantibioticsuseandresistance.Programs for the management of bacterial resistance usuallyincludemodificationsofantibioticuse,especiallyinthede-creaseduseofciprofloxacinandthethird-generationcepha-losporins. Physicians training should be an important part ofeffortsagainstantibioticresistance.Nationalguidelinesonthistopic,aswellasgooddiagnosticandtherapeuticproto-colsareimportant.Arationalandstrictantibioticpolicyis,thus, of great importance for the optimal use of these agents.The obtained results are the basis for further analysis ofbacterialresistanceincorrelationwithantibioticconsump-tion in the Clinical Center Ni in Serbia.Strana 312 VOJNOSANITETSKI PREGLED Volumen 66, Broj4Velikovi-Radovanovi R, et al. Vojnosanit Pregl 2009; 66(4): 307312.R E F E R E N C E S1.Vlahovi-PalcevskiV,MoroviM,PalcevskiG,Betica-RadiL.An-timicrobial utilization and bacterial resistance at three differenthospitals. Eur J Epidemiol 2001; 17(4): 37583.2.RaymondDP,PelletierSJ,SawyerRG.Antibioticutilizationstrategiestolimitantimicrobialresistance.SeminRespirCritCare Med 2002; 23(5): 497501.3.Willemsen I, Groenhuijzen A, Bogaers D, Stuurman A, van Keulen P,KluytmansJ.Appropriatenessofantimicrobialtherapymeas-uredbyrepeatedprevalencesurveys.AntimicrobAgentsChemother 2007; 51(3): 8647.4.Ballow CH, Schentag JJ. Trends in antibiotic utilization and bac-terialresistance.ReportoftheNationalNosocomialResis-tanceSurveillanceGroup.DiagnMicrobiolInfectDis1992;15(2 Suppl): 37S42S.5.Urbnek K, Kolr M, Strojil J, Koukalov D, Cekanov L, Hejnar P.Utilization of fluoroquinolones and Escherichia coli resistanceinurinarytractinfection:inpatientsandoutpatients.Pharma-coepidemiol Drug Saf 2005; 14(10): 7415.6.GulbinovicJ,MyrbckKE,BytautienJ,WettermarkB,StruweJ,Bergman U. Marked differences in antibiotic use and resistancebetweenuniversityhospitalsinVilnius,Lithuania,andHud-dinge, Sweden. Microb Drug Resist 2001; 7(4): 3839.7.YatesRR.Newinterventionstrategiesforreducingantibioticresistance. Chest 1999; 115(3 Suppl): 24S27S.8.Rice LB. Controlling antibiotic resistance intheICU:differentbacteria,differentstrategies.CleveClinJMed2003;70(9):793800.9.PattersonJE,HardinTC,KellyCA,GarciaRC,JorgensenJH.As-sociation of antibiotic utilization measures and control of mul-tiple-drugresistanceinKlebsiellapneumoniae.InfectControlHosp Epidemiol 2000; 21(7): 4558.10.Kiivet RA, Dahl ML, Llerena A, Maimets M, Wettermark B, BereczR.Antibioticusein3Europeanuniversityhospitals.ScandJInfect Dis 1998; 30(3): 27780.11.GoryachkinaK,BabakS,BurbelloA,WettemarkB,BergmanU.Qualityuseofmedicines:anewmethodofcombiningantibi-oticconsumptionandsensitivitydata-applicationinaRussianhospital. Pharmacoepidemiol Drug Saf 2008; 17(6): 63644.12.Goossens H, Ferech M, Vander Stichele R, Elseviers M. ESAC Proj-ect Group. Outpatient antibiotic use in Europe and associationwithresistance:across-nationaldatabasestudy.Lancet2005;365(9459): 57987.13.WHO.ATCindexwithDDDs.WorldHealthOrganisation:World Health Organisation Collaborating Cente for Drug Sta-tisticsMethodology;20032005.[accesed2008june28].Avalaible from: www.whocc.no/atcddd.14.WHOGlobalStrategyforContainmentofAntimicrobialRe-sistance.[accesed2008june28].Avalaiblefrom:http://www.who.int/csr/drugresit/guidance/en15.NationalCommitteeforClinicalLaboratoryStandards.Methodsfordilution antimicrobial susceptibility tests for bacteria that growaerobically.ApprovedstandardM7-A6.NationalCommitteefor Clinical Laboratory Standards;2007.16.MochizukiT,OkamotoN,YagishitaT,TakuhiroK,MashikoK,OgawaF,etal..AnalysisofantimicrobialdrugresistanceofStaphylococcusaureusstrainsbyWHONET5:microbiologylaboratorydatabasesoftware.JNipponMedSch2004;71(5):34551.17.HusseinABataineh,KhalidMAlrashed.Resistantgram-negativebacilli and antibiotic consumption in Zarqa, Jordan. Pak J MedSci 2007; 23 (1 ): 5963.18.HermosillaNjeraL,CanutBlascoA,UlibarrenaSanzM,AbasoloOsinaga E, Abecia Inchaurregui LC. Trends in antimicrobial utili-zationataSpanishgeneralhospitalduringa5-yearperiod.Pharmacoepidemiol Drug Saf 2003; 12(3): 2437.19.Vlahovi-Palcevski V, Dumpis U, Mitt P, Gulbinovic J, Struwe J, Pal-cevski G, et al. Benchmarking antimicrobial drug use at univer-sity hospitals in five European countries. Clin Microbiol Infect2007; 13(3): 27783.20.Velikovi Radovanovi R, Koci B, Lili R, Petrovi J, An-tiS.Antibioticutilizationandthedevelopmentofbacterialresistance.Amstermad:InternationalProceedingsDivision;2007. pp 15356.21.Willemsen I, Groenhuijzen A, Bogaers D, Stuurman A, van Keulen P,KluytmansJ.Appropriatenessofantimicrobialtherapymeas-uredbyrepeatedprevalencesurveys.AntimicrobAgentsChemother 2007; 51(3): 864-7.22.PolkRE,FoxC,MahoneyA,LetcavageJ,MacDougallC.Meas-urementofadultantibacterialdrugusein130UShospitals:comparison of defined daily dose and days of therapy. Clin In-fect Dis 2007; 44(5): 66470.23.MacDougallC,PowellJP,JohnsonCK,EdmondMB,PolkRE.Hospital and community fluoroquinolone use and resistance inStaphylococcus aureus and Escherichia coli in 17 US hospitals.Clin Infect Dis 2005; 41(4): 43540.24.Lepper PM, Grusa E, Reichl H, Hgel J, Trautmann M. Consump-tionofimipenemcorrelateswithbeta-lactamresistanceinPseudomonasaeruginosa.AntimicrobAgentsChemother2002; 46(9): 29205.25.PatersonDl,MutoCa,GrossP,NdiranguMw,KuznetsovD,HarrisonLh.Doesthe"DefinedDailyDose"(DDD)Ade-quately Measure Antibiotic Utilization in Hospitalized PatientsinTertiaryMedicalCenters?AbstrIntersciConfAntimicrobAgentsChemotherIntersciConfAntimicrobAgentsChemo-ther 2002; 42.26.Atntibioticsandantimicrobialtherapy.Avalaiblefrom:http://www. antibiotic.ru/index.php?newlang=eng27.Davey P, Brown E, Fenelon L, Finch R, Gould I, Hartman G, et al.Interventionstoimproveantibioticprescribingpracticesforhospital inpatients. Cochrane Database SystRev CD003543;2005.The paper received on October 3, 2008.