AnalysisofthePatientswithSepsis CausedbyGramPositiveand GramNegativeBacteria

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1 ORİJİNAL ARAŞTIRMA AnalysisofthePatientswithSepsis CausedbyGramPositiveand GramNegativeBacteria Pınar TURAN, MD, a Özlem TANSEL, MD, a Galip EKUKLU, MD, b Aygül DOĞAN ÇELİK, MD a a Department of Infectious Diseases and Clinical Microbiology, b Department of Public Health Trakya Universty, Faculty of Medicine, Edirne Ge liş Ta ri hi/received: Ka bul Ta ri hi/accepted: Ya zış ma Ad re si/correspondence: Özlem TANSEL, MD Trakya Universty, Faculty of Medicine, Department of Infectious Diseases and Clinical Microbiology, Edirne, TÜRKİYE/TURKEY otansel@yahoo.com KeyWords:Sepsis;riskfactors ABSTRACTObjective:Theobjectiveofthisstudywastoevaluatetheepidemiological,clinical, laboratoryfeaturesandriskfactorsassociatedwithmortalityofthe109adultcasesofsepsisin whichgrampositive,andgramnegativebacteriaisolatedfrombloodcultures.materialandmethods:onehundredandninepatientswithsepsisfollowedinourhospitalbetweenjanuary2002 andjanuary2003wereinvestigatedprospectively.results:gramnegativebacteriawereisolatedfrombloodculturesintherateof58.7%.themostfrequentgramnegativebacteriumwas Escherichiacoli,andgrampositivewasStaphylococcusaureus.Statisticallysignificantdifferencewasnotdetectedbetweengrampositive,andgramnegativebacteriasepsisrelatedwith developmentofhypothermia,appropriateantibiotictreatment,septicshock,multipleorgan dysfunctionsyndrome(mods),disseminatedintravascularcoagulation(dic),andmortalityrate.themortalityratewas23%.theriskfactorsrelatedwithmortalitywereoldage,hypothermia,stayinginintensivecareunits,changesinconsciousness,septicshock,mods,dic,renal failure,acuterespiratorydistresssyndrome(ards),inappropriateantibiotherapy,andlackof infectiousdiseasespecialistconsultation.inappropriateantibiotictherapy,severesepsis,andold agewerefoundasindependentfactorsinmortalitybylogisticregressionanalysis.conclusion: Therewasnosignificantdifferencebetweentheriskfactorsofgrampositive,andgramnegativebacteriasepsis.Promptdiagnosisandappropriateantibiotictreatmentwasimportantindecreasingthemortalityinbothofthem. ÖZETAmaç:Buçalışmanınamacıkankültürlerindegrampozitifvegramnegatifbakteriüreyen109erişkinsepsisolgusununepidemiyolojik,klinik,laboratuvarözelliklerinivemortalite ileilişkiliriskfaktörlerinideğerlendirmektir.gereçveyöntemler: HastanemizdeOcak2002- Ocak2003tarihleriarasındaizlenen109sepsishastasıprospektifolarakaraştırılmıştır.Bulgular:Kankültürlerinin%58.7 sindegramnegatifbakteriizoleedildi.ensıkgramnegatifbakteri Escherichiacoli veensıkgrampozitifbakteristaphylococcusaureus idi.grampozitifvegram negatifbakterilerarasındahipotermi,uygunantibiyotiktedavisi,septikşok,multiplorgandisfonksiyonsendromu(mods),yaygındamariçipıhtılaşması(dic)vemortaliteoranlarıileilişkiliolarakistatistikselfarksaptanmadı.ölümoranı%23idi.mortaliteyleilişkiliriskfaktörleri; ileriyaş,hipotermi,yoğunbakımdabulunmak,bilinçdeğişikliği,septikşok,mods,dic,böbrekyetmezliği,akutsolunumyetmezliğisendromu(ards),uygunsuzantibiyotikkullanımı, enfeksiyonhastalıklarıuzmanıkonsültasyonuolmayışıydı.uygunsuzantibiyotiktedavisi,ağır sepsisveileriyaşlojistikregresyonanalizindeölümleilişkilibağımsızriskfaktörleriolarakbulundu.sonuç: Riskfaktörleriyönündengrampozitifvegramnegatifbakterisepsisiarasındaanlamlıfarkyoktu.Herikisindedehızlıtanıveuygunantibiyotiktedavisimortaliteazalmasında önemliydi. AnahtarKelimeler: Sepsis;riskfaktörleri Cop yright 2008 by Tür ki ye Kli nik le ri TurkiyeKlinikleriJMedSci2008;28(6):791-7 TurkiyeKlinikleriJMedSci2008;28(6) 791

2 Turanveark. epsisisseeninanincreasingrateanditsmortalityisstillhigh.increaseofoldageinthe society,lengtheningofthesurvivalofthepatientswithchronicdiseases,broaduseofimmunosuppressive therapy, increase of invasive proceduresindiagnosisandtreatmentarethecausesinincreasedrateofsepsisincidence. 1 Mortality ratehasbeenreportedasbetween12%and80%by differentstudiesanditsaveragerateisabout35%. 2 Determinationofthemortalityfactorsinsepsisis veryimportant. Weinvestigatedtheepidemiological,clinical andlaboratoryfeaturesofthe109adultcasesof sepsisinwhichgrampositiveandgramnegative bacteriaisolatedfrombloodculturesandevaluated theriskfactorsassociatedwithmortalityinthis study. MA TE RI AL AND MET HODS Allpatientshospitalizedinourhospitalbetween January2002andJanuary2003withsepsisassociatedwithpositivebloodculturesinwhichgram positive,andgramnegativebacteriaisolatedwere included in this prospective study. The patients werefolloweduntildeathordischargefromhospital.thestudywasperformedafterpermissionfrom thelocalcommitteeofethicsinscienceandaccordingtotheguidelinesofthehelsinkiiideclaration.thepatientswithpositivebloodculturesfor Brucellaspp.,andpotentiallyskincontaminants; andyoungerthan18yearsoldwereexcludedfrom thestudy. Blood was inoculated into BACTEC aerobic bottles. The bottles were incubated in BACTEC 9240 blood culture systems (Becton Dickinson, Sparks,MD,USA)untilflaggedaspositiveorseven days.whenbloodculturesbecamepositive,the broth was gram- stained, and sub cultured onto sheepbloodagar,andchocolateagarplates.theorganismswereidentifiedusingstandardconventionalmethods. 3 Truebacteremiaorcontamination:Eachpositivebloodculturewasassessedandcategorizedas true-positivesorcontaminantsafterthefollowing EnfeksiyonHastalıkları factorsweretakenintoaccount;thepatient sclinicalhistory,physicalfindings,bodytemperature atthetimeofbloodculture,leukocytecount,numberofpositivebloodculturesoutofthetotalnumber performed, results of cultures of specimens from other sites, imaging results, clinical course andresponsetotherapy. 2,4 Episode:Anepisode ofbacteremiawasdefined byfirstpositivebloodculturewasacceptedasasingleepisode.anynewpositivebloodcultureresult thatoccurred>48hoursafterthepreviousresult wasacceptedasaseparateepisodeifitwasclear thattheonewasnotpartofthesameepisodeaccordingtotheclinicalcourse. 4 Hospital-acquiredsepsis:Thepatientswithoutclinicalsymptoms,andsignsofsepsisonadmission to the hospital; and with positive blood culturesafter72hoursofhospitalizationwerediagnosedasnosocomialsepsisaccordingtothecriteria of Centers for Disease Control and Prevention (CDC). 4,5 Community-acquiredsepsis:Thepatientswith clinicalsymptoms,andsignsofsepsisonadmission tothehospital;andpositivebloodculturesin72 hoursofhospitalizationwerediagnosedas community-acquired sepsis according to the criteria of CDC. 5 Transientbacteremia:Thepatientswithpositivebloodculturewhohadnotsymptomsandsigns oflocalinfectionandsymptoms;andsignsofsymptomsresolvedtotallyin24hourswereacceptedas transientbacteremia. 6 Underlyingdiseases:Underlyingdiseaseswerecategorizedasrapidlyfatal(groupI),fatalinthe end(groupii),nonfatal(groupiii)accordingtothe McCabeandJacksonclassification. 7,8 Appropriateantimicrobialtherapy:Theantibiotherapywasacceptedasappropriateiftheisolated bacteria was susceptible to at least one antibioticinvitro,beginningtimeoftheantibiotherapywasin24hoursafterbacteriaisolation;appropriatedurationanddose. 4 Outcome:The patients are classified in two groupsastheonesdischargedfromhospitalwith 792 TurkiyeKlinikleriJMedSci2008;28(6)

3 InfectiousDiseases clinicalimprovement,andtheoneswithfatalend duetobacteremiaorclinicaldeteriorationbecause ofbacteremia. Theclassificationofthebacteremiawasmade accordingtothedefinitionsbelow: Patients clinicalstatuswasdefinedassepsis, severesepsis,septicshockandmodspreviously described. 9 Statisticalanalysis S0064MINITABrelease13programwasusedin statisticalanalysis.datawereanalyzedbyχ 2,Fisher sexacttest,mannwhitneyutest.independentvariablesrelatedwithmortalitywithapvalue <0.05intheunivariateanalyseswereenteredinto beginingofthestepwiselogisticregressionmodels. Theoddsratios,95%confidenceintervals(CI),and pvalueswerecalculatedforeachriskfactorinthe finalmodels. Thevalueofp<0.05wasacceptedas statisticallysignificant. RE SULTS Weidentifiedatotalof109patientswithsepsis whowerefollowedupinourhospitalbetween January2002,andJanuary2003.Isolatedbacteria from blood cultures were gram negative in 64 (58.7%),andgrampositivein45(41.3%)patients. E.coliandotherEnterobactericiaewerethemost Turanetal frequentisolatedgramnegativeorganisms.the otherisolatedgramnegativemicroorganismswereacinetobacterspp.,pseudomomasaeroginosa. Staphylococcus aureus accounted for the most frequentisolatedgrampositiveorganism.theothergrampositivemicroorganismswereenterecoccus spp., Streptococcus spp., coagulase negative staphylococcus (CNS). The origin of grampositivebacteremiawasvascularcatheterin therateof31%andtheoriginofgramnegative bacteremiawasgenitourinarysystemintherate of42%.thehospitalacquiredbacteremiaaccountedforhigherratethancommunityacquired bacteremiainbothofthegrampositive(60%), andgramnegative(58%)bacteremia.thedevelopmentofhypothermia,shock,mods,dic,and useofappropriateantibiotictreatmentwerenot statisticallydifferentbetweengrampositive,and gramnegativebacteremia(p>0.05).therateof mortality in gram positive, and gram negative bacteremia was 28.9%, and 20.3% respectively butthisdifferencewasnotstatisticallysignificant (p>0.05)(table1). Whenconsideringtotal109caseswithsepsis 68(62%)ofthepatientsweremale;41(38%)of themwerefemale.thisdifferencewasfoundstatisticallysignificant(p<0.001).themeanageof thepatientswas60.0±18.4(18-93).ninetyone TABLE 1: Comparison of the features of the patients with gram positive and gram negative bacteremia. Gram (+) Bacteremia Gram (-) Bacteremia n % n % The origin of the bacteremia Respiratory 18 (40) 21 (33) Genitourinary 1 (2) 27 (42)* Vascular catheter 14 (31)* 1 (2) The source of the bacteremia Hospital 27 (60) 37 (58) Community 18 (40) 27 (42) Hypothermia 5 (11) 2 (3) Appropriate antibiotherapy 33 (73) 50 (78) Shock 10 (22) 15 (23) MODS 5 (11) 6 (9) DIC 9 (20) 11 (17) Mortality 13 (29) 13 (20) *p< 0.05 MODS: Multiple Organ Dysfunction Syndrome, DIC: Disseminated Intravascular Coagulation. TurkiyeKlinikleriJMedSci2008;28(6) 793

4 Turanveark. EnfeksiyonHastalıkları (83.5%)ofthemwasolderthan40yearsold.This finding was statistically significant (p< 0.001). Hospital acquired bacteremia accounted for 58.7%ofthetotalcases,andthiswasfoundstatisticallysignificant(p<0.001).Themostfrequent originofinfectionincommunityacquiredbacteremia,andhospitalacquiredbacteremiaweregenitourinary system in the rate of 33.3%, respiratorysystemintherateof45.3%respectively.themostfrequentisolatedagentsfrombloodculturesincommunityacquiredbacteremia, andhospitalacquiredbacteremiawase.coli,and S.aureusrespectively. Underlyingdiseaseswere ingroupi,groupii,andgroupiiiintheratesof 2.8%,39.4%,and57.8%respectively.Underlying disease,thesourceofthebacteremia,andneutropeniawerenotstatisticallysignificantriskfactorsrelatedwiththedevelopmentofshock,dic, andmods(p>0.05).septicshockwasseenmorefrequentlyinthepatientswithards,mods, anddic(p<0.05). Crudemortalityofthepatientswithbacteremiawasdetectedas23%.Evaluationoftherisk factorsinthemortalityispresentedintable2. Statisticallysignificantriskfactorsrelatedwith mortalityweredetectedasoldage,hypothermia,highrespiratoryrate,highlevelofbloodurea, hospitalizationintheintensivecareunit,changesinconsciousness.mortalityrateinthepatients was also high in the patients with shock, MODS,DIC,renalfailure,andARDS(p<0.05). Appropriateantibiotictherapywasgivenin83 (76.1%)ofallthepatients.Theappropriateantibiotictherapywasinhigherrate(86%)inthepatientswithcommunityacquiredsepsisthanthe oneswithhospitalacquiredsepsis(68%).thisresultwasfoundasstatisticallysignificant(p<0.05). Septicshock,MODS,andDICwasseeninthepa- TABLE 2: Risk factors related with mortality due to the bacteremia. Risk factor Episode Mortality p n n (%) Sex Male (22.1) Non-significant Female (26.8) Unit Internal medicine (21.3) Non-significant Surgical 21 4 (19) Non-significant Intensive care 8 5 (62.5) < 0.05 Source of bacteremia Hospital (26) Non-significant Community 45 9 (20) Non-significant Type of bacteremia Gram (+) (28.9) Non-significant Gram (-) (20.3) Non-significant Underlying disease Group I 3 1 (33.3) Non-significant Group II (25.6) Non-significant Group III (22.2) Non-significant Neutropenia Present 6 2 (33.3) Non-significant Consciousness changes Present (58.3) < Shock Present (60) < MODS Present 11 9 (81.8) < DIC Present 20 9 (45) < 0.05 Renal failure Present (54.5) < Hepatic failure Present 15 5 (33.3) Non-significant ARDS Present (85.7) < Inappropriate antibiotherapy Present (57.7) < Infectious diseases consultation Present (34.9) < ARDS: Acute Respiratory Distress Syndrome, MODS: Multiple Organ Dysfunction Syndrome, DIC: Disseminated Intravascular Coagulation. 794 TurkiyeKlinikleriJMedSci2008;28(6)

5 InfectiousDiseases tients with inappropriate antibiotic therapy in higher rates (p< 0.05), and mortality was also highinthesepatients(p<0.001).therateofmortalitywashighinthepatientsgiveninappropriate antibiotic therapy (p< 0.001). The rate of appropriateantibiotictreatmentwashighinthe patientswhowereseenbyaninfectiousdiseases specialist(p<0.05).themortalityofthepatients werehighinpatientswhowerenotseenbyan infectiousdiseasesspecialist,andthiswasstatisticallysignificant(p<0.05).variablesassociated withoutcomewithapvalue<0.05intheunivariateanalysesandvariablesconsideredclinically significant(age,appropriateantibiotictherapy, severesepsis,underlyingdisease, hospitalization intheintensivecareunit)wereenteredintobeginingofthestepwiselogisticregressionmodels formortalitytoidentifyindependentriskfactors. Inappropriate antibiotic therapy, severe sepsis, oldagewasfoundasindependentriskfactorsin mortality according to the logistic regression analysis(table3). DIS CUS SI ON Severalbacteriaareresponsiblefortheetiologyof the sepsis. Although the streptococci, and the staphylococciwerethemostcommoncausesof bacteremiabeforetheantibioticeragramnegativebacteriahavebeenisolatedmorefrequentlyin sepsisinrecentyears,andalsotherateofgram positivebacteriaintheetiologyofsepsishasbeen increasedinlastdecade. 10 Asthecausativeagents insepsisgramnegativebacteria,andgrampositi- vebacteriahasbeenreportedintheratesof20-64%,and27-74%respectively. 1 Wefoundgram negativebacteriaintherateof58.7%,andgram positivebacteriaintherateof41.3%inourstudy. ThemostfrequentlyisolatedpathogenswereE. TABLE 3: Independent risk factors related with mortality. Risk factors OR 95% CI p Inappropriate antibiotherapy < 0.05 Severe sepsis < 0.05 Age < 0.05 OR: Odd s ratio, CI: Confidence interval. Turanetal coli(26.4%), and S. aureus(22.9%).inthestudyof Geerdesetal E. coli (26.4%),S. aureus(18.9%), andotherentericbacilli(15.2%)werethemost frequentagentsisolatedinthepatientswithsepsis. 11 SENTRYantimicrobialsurveillanceprogram organizedin25universityhospitalsofeuropein the years of reported the S. aureus (17.6%),coagulasenegativestaphylococci(17.1 %),andotherentericbacilli(14.1%)asthemost frequentmicroorganismsafterthee.coli insepsis. 12 Mortalityofthesepsisduetogrampositive bacteriawasreportedinhigherrate(25.5%)than thegramnegativebacteria(18.3%)inastudymadeinberlin. 11 Inanotherstudymadeabouthospitalacquiredsepsismortalityrelatedwithgram negativebacteremia,andgrampositivebacteremiawasreportedas26.2%,and11.6%respectively. 4 Althoughwefoundtherateofmortalityin sepsisrelatedwithgrampositivebacteriawasfoundhigherthanthegramnegativebacteriathis differencewasnotdetectedasstatisticallysignificant.vallesetalfoundthatthesepticshockdevelopmentingramnegativebacteremiawasmore frequentthanthegrampositivebacteremiabut thisdifferencewasnotfoundinthestudiesmade byleibovicietalandgeerdesetal Wealsofound that the complications such as septic shock, MODSandDICdevelopedinsimilarratesinsepsisduetogrampositiveandgramnegativebacteria. 4,11,13 Themortalityrateoftotal109caseswithsepsiswasfoundas23%inourstudy.Wedetected oldage,hypothermia,highrespiratoryrate,high levelofbloodurea,changesinconsciousnessstatus,developmentofshock,mods,dic,ards, renalfailure,inappropriateantibioticuse,absenceofinfectiousdiseasesconsultationastherisk factorsrelatedwithmortality.independentrisk factorsrelatedwithmortalitywerefoundasold age,severesepsis,andinappropriateantibioticuse bylogisticregressionanalysis.sex,underlyingdisease,neutropenia,leukocyte,thrombocytecount, liverfailurewasnotfoundstatisticallysignificant riskfactorsinmortality.oldageandmetabolic, neoplastic,andimmunosuppressivediseasespre- TurkiyeKlinikleriJMedSci2008;28(6) 795

6 Turanveark. disposetheinfectiousdiseases.severalstudiesrelatedwithprognosisofbacteremiadetectedthe mortalityrateashighintheoldagepatients. 2,4,14,15 Someauthorsdidnotfindsucharelation. 6,16 Mortalitywasdetectedinhighrateinoldpatientsin ourstudy.primary,andsecondaryhumoralimmunodeficiency,underlyingdiseasesinoldage patientsarenotonlypredisposingfactorsinbacteremiabutalsocausessevereoutcomeandincreasedmortality. Microorganismscausingbacteremiadiffersaccordingtothehospitalandcommunityacquired bacteremia.theetiologicagentsofhospitalacquiredsepsisarediffersamongcountries,hospitals, andalsounitsinthesamehospital. Weinsteinetalreportedthehospitalacquired bacteremiaintherateof50%,anddetecteds.aureus,cns,enterecoccusspecies,p.aeruginosa,and other nonfermentative bacteria as the causative agentsinhospitalacquiredsepsis. 17 Themostfrequentagentsisolatedincommunityacquiredbacteremiawere S.aureus,S. pneumoniae,e. coliand otherentericbacilli. E.coli and S.aureuswerefoundasthemostfrequentagentsincommunityacquired, and hospital acquired bacteremia respectivelyinourstudy.themortalityrateishigherinhospitalacquiredbacteremiathancommunityacquiredbacteremiaaccordingtotheseveral studies. 6,17-19 Wedidnotfindanydifferencebetweenthem.Highermortalityratewasdetectedin thepatientsofintensivecareunitthantheonesin surgeryandinternalunits,andthisdifferencewas statisticallysignificantasinanotherstudy. 16,18,20 A lotofinvasiveproceduresperformed,andinfectionswithantibioticresistantisolatesinintensivecareunitweresuggestedfactorsasthecauseofthis highmortalityrate. Bodytemperatureelevatesinmostofthepatientswithsepsis.Hypothermiahasbeenreportedas2.8-8%inseveralstudies. 6,17,20 Wefound thisrateas6.4%,andhypothermiaisapredisposingfactorinincreasingmortalityasinotherstudies. 6,17,20 While neutropenia is an important factorinincreasingmortalityinsomestudiesit hasbeenfoundinsignificantinourstudy. 4,6,14,17 EnfeksiyonHastalıkları Septicshockdevelopmentisoneofthemostseverecomplicationsinbacteremia.Therateofsepticshockhasbeenreportedas10.5%and20.9% byleibovici,andgogosrespectively. 13,15 Uzunet al foundthisrateas19.5%ingramnegativebacteremia. 6 Thesepticshockwasdetectedintherate of 22.9% in our patients. Leibovici et al also foundthatrenalfailure,ards,mods,dic,hepaticfailurecomplicationswereseenmorefrequentlyinthepatientswithsepticshock. 13 Wealso foundsamecomplicationsexcludinghepaticfailureinhighrateinthesepatients.septicshockincreasesthemortalityratesignificantly,andhas beenreportedas56-82%. 4,13,16,20 Wealsodetected thisdatainourstudy.dicisanotherseverecomplicationofthebacteremia.itsrateis5%inhospitalacquiredbacteremiaaccordingtoreportof Vallesetal,and37%accordingtotheGogoset al. 4,15 Wedetectedthisrateas18.3%intotal109 caseswithhospital,andcommunityacquiredsepsis.sepsisisseenrarelyinhealthypeople.there isusuallyapredisposingfactororanunderlying disease.underlyingdiseasehasbeenreportedas animportantfactorinprognosisofbacteremia. Mortalityratewasfoundassignificantlyhighin thepatientswhowereinthegroupsofdiseases thatwererapidlyfatal,andfatalintheendaccordingtothemccabeandjacksoncriteriainseveralstudiesperformedin , , and1998theprognosis. 17,20,21 Anotherstudyfrom Turkey and we did not find a relationship like thosefindings. 6 Besidespromptdiagnosis,andtreatmentofthe sepsis, source of the sepsis, probable causative agents,andantibioticsusceptibilityoftheseagents were important factors in the accurate managementofthetherapy.appropriateantibiotictherapyaccountsforthemajorroleinthesuccessful treatmentofthesepsis. 6,9,17,22,23 Therateofthepatientsgivenappropriateantibiotictherapywassignificantly high in the ones who were seen by infectiousdiseasesspecialist,anddiagnosedascommunityacquiredbacteremia.becausetheantibiotic resistance rate of the etiologic agents in communityacquiredbacteremiaislowerthanhos- 796 TurkiyeKlinikleriJMedSci2008;28(6)

7 InfectiousDiseases pitalacquiredbacteremia. 22 Inhospitalacquired bacteremiatheprobableetiologicagents,andantibioticresistancepatternisconsideredbetterbyan infectiousdiseasesspecialist.thesignificantlyhigh rateofmortality,developmentofshock,mods, anddicinthepatientsofsepsiswithinappropriateantibiotictherapyshowsthatappropriateantibiotic therapy is very important in bacteriemic patients. CONC LU SI ONS Turanetal Sepsisisaclinicalprocesswithhighmortality,and morbidityanditsmortalitydecreaseswithprompt diagnosis,andtreatment.earlydiagnosis,isolation ofthecausativeagentofthebacteremia,anddetectionoftheantimicrobialsusceptibilitywerethe importantfactorsinthemanagementofthetherapy,andsurvivalinsepsis. REFERENCES 1. Munford RS. Sepsis, severe sepsis, and septic shock. In: Mandell GL, John E. Bennett JE, Dolin R., eds. Mandell, Douglas and Bennett s Principles and Practice of Infectious Diseases. 6th ed. Philadelphia: Churchill Livingstone; p Pittet D, Li N, Woolson RF, Wenzel RP. 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