Non-HACEK Gram-negative bacillus endocarditis

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Médecineetmaladiesinfectieuses49(2019)616–620

Short

communication

Non-HACEK

Gram-negative

bacillus

endocarditis

Endocardite

à

bacilles

à

Gram

négatif

non

HACEK

M. Ertugrul

Mercan

a

,

F. Arslan

b,∗

,

S. Ozyavuz

Alp

c

,

A. Atilla

d

,

D. Seyman

e

,

G. Guliyeva

f

,

B. Kayaaslan

g

,

S. Sari

h

,

B. Mutay

Suntur

i

,

B. Isik

b

,

A. Mert

j

a_Department_of_Cardiology,_Faculty_of_Medicine,_Istanbul_Acibadem_University,_Istanbul,_Turkey

b_Department_of_Infectious_Diseases_and_Clinical_{Microbiology,}_Faculty_of_Medicine,_Istanbul_Medeniyet_University,_Istanbul,_Turkey c_Department_of_Infectious_Diseases_and_Clinical_{Microbiology,}_Faculty_of_Medicine,_Hacettepe_University,_Ankara,_Turkey d_Department_of_Infectious_Diseases_and_Clinical_{Microbiology,}_Faculty_of_Medicine,_Ondokuz_Mayis_University,_Samsun,_Turkey

e_Department_of_Infectious_Diseases_and_Clinical_{Microbiology,}_Health_Sciences_University,_Antalya_Education_and_Training_Hospital,_Antalya,_Turkey f_Department_of_Infectious_Diseases_and_Clinical_{Microbiology,}_Faculty_of_Medicine,_Ege_{University, ˙Izmir,}_Turkey

g_Department_of_Infectious_Diseases_and_Clinical_{Microbiology,}_Faculty_of_Medicine,_Yildirim_Beyazit_University,_Ankara,_Turkey h_Department_of_Intensive_Care_Unit,_Health_Sciences_University,_Turkiye_{Yüksek ˙Ihtisas}_Taining_and_Research_Hospital,_Ankara,_Turkey i_Department_of_Infectious_Disease_and_Clinical_{Microbiology,}_Health_Sciences_University,_Adana_Numune_Taining_and_Research_Hospital,_Adana,_Turkey

j_Department_of_Infectious_Diseases_and_Clinical_{Microbiology,}_Faculty_of_Medicine,_Istanbul_Medipol_University,_Istanbul,_Turkey

Received18September2018;receivedinrevisedform16November2018;accepted12March2019 Availableonline30March2019

Abstract

Patientsandmethods.–Retrospectiveanalysisofclinicaldatausing26diagnosednon-HACEKGram-negativeinfectiveendocarditiscases fromninehospitalsinTurkey.

Results.–Meanageofpatientswas53(28–84)years,witha23%casefatality.Nineteen(73%)ofthe26patientshadatleastonepredisposing factor.Thepresenceofacentralvenouscatheterwasthemostcommonpredisposingfactor(7/26patients).Pseudomonasaeruginosa(7/26patients) andEscherichiacoli(7/26patients)werethemostcommonpathogens.Themediandurationoftheantibiotictherapywas42days(range3–84 days).Surgicalprocedureswereperformedin10patients.Thecasefatalitywassimilarinpatientswhodidordidnotundergosurgery(20%vs. 25%).

Keywords: Endocarditis;Catheterization;Gram-negativebacteria

Résumé

Patientsetméthodes.–Analyserétrospectivedesdonnéescliniquessur26casd’endocarditeinfectieuseàbacillesàGramnégatifnonHACEK dansneufhôpitauxturcs.

Résultats.–L’âgemoyendelacohortedepatientsétaitde53ans(28–84ans).Lalétalitéétaitde23%.Parmiles26patients,19(73%)avaientau moinsunfacteurprédisposant.Laprésenced’uncathéterveineuxcentralétaitlefacteurprédisposantleplusfréquent(7/26patients).Pseudomonas aeruginosa(7/26patients)etEscherichiacoli(7/26patients)étaientlespathogèneslesplusfréquents.Laduréemédianedel’antibiothérapieétait de42jours(3à84jours).Desinterventionschirurgicalesontétéréaliséeschez10patients.Lalétalitéétaitsimilairechezlespatientsayantounon subiuneinterventionchirurgicale(20%vs25%).

Motsclés:Endocardite;Cathétérisme;BactériesàGramnégatif

∗_{Corresponding}_author._Ist._Medeniyet_Univ,_Goztepe_EA_Hastanesi,_Dr._Erkin_caddesi,₃₄₇₂₂_Kadıkoy_Istanbul,_Turkey.

E-mailaddress:ferhatarslandr@hotmail.com(F.Arslan).

https://doi.org/10.1016/j.medmal.2019.03.013

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1. Introduction

Infectiveendocarditis(IE)isanuncommonbutsevere infec-tionassociatedwithhighmorbidityandcasefatality[1].Despite improvementsinhealthcareandtreatmentoptions,thediagnosis andmanagement of IE remain challenging. Viridans strepto-cocciandStaphylococcusaureusarethemostcommonbacterial agentsofIE,followedbyenterococciandHACEKgroup bac-teria[2–5].Gram-negativebacteriararelycauseIEbecauseof their relatively lowendocardial affinity.The frequencyof IE due to non-HACEK Gram-negative bacteria was reported at approximately1%inamultinationalstudy[6].

Intravenous drug use has been considered for decades as themostcommonpredisposingfactorfornon-HACEK Gram-negativeIEuntilrecentstudiesandregistriesreporteddifferent results [6–8]. Increasing vascular catheterization and elderly population may be new risk factors for non-HACEK Gram-negativeIE.

Dataon non-HACEK Gram-negativeIE islimited to case reportsandcaseseries.Thereisaneedfor morestudies con-sideringtheincreasingandchangingepidemiologicalrisk.We aimedtocontributetothereportofclinicalcharacteristics, mana-gement,andoutcomeofnon-HACEKGram-negativeIE.

2. Methods

Weperformedaretrospective,multicenter,andobservational studybetween2007and2016.Adultpatientswithadiagnosis ofnon-HACEKGram-negativeIEwereincludedinthestudy. Individualpatientfilesweresearchedtoobtaindemographicand clinicaldata.Usingemails,weinvitedinfectiousdisease spe-cialiststotakepartinthestudy.Ninetertiaryhospitalsagreedto participate.Hospitalsweresentacaserecorddatafile(Microsoft Excelform)andwereaskedtofillitout.Thefollowingdatawas obtainedforallpatients presentingwithGram-negative endo-carditis: age, gender,known predisposing factors, symptoms, clinicalpresentation,echocardiogramfindings,microbiological testresults,treatment preferences,complications, andhistory of drug use. Participating hospitalswere asked toreport any otherendocarditiscaseobservedoverthepast10yearsandthe proportionofGram-negativeendocarditiscaseswascalculated. Followingobtentionofdatarecords,thediagnosisofpatients wasreviewedaccordingtothemodifiedDukecriteria[9].Ten patientswereexcludedfromthestudy:fourbecauseofalackof echocardiogramfindings,andsixbecauseof theidentification ofendemicpathogens(Brucella)andHACEKgroupbacteria.

Numericaldataispresentedasmean±SDormedian(IQR andrange).Categoricaldataispresentedasnumberand percent-age.

3. Results

3.1. Patients’characteristics

Twenty-sixpatients(53±14years[range:28–84],15[58%] females)presentingwithnon-HACEKGram-negativeIEwere assessed. Nineteen (73%) of them had at least one of the

predisposing factors considered in the study. None of them wereintravenous drugusers. Onepatienthadahistoryof IE. Rheumatic valve disease (n=4) and prosthetic valves(n=2) werethemostfrequentstructuralvalvediseases.Demographic, clinical, and treatment features of the study population are detailedinTable1.

All26caseswereconfirmedasdefiniteendocarditis accord-ingtothemodifiedDukecriteria:26(100%)wereconfirmedby bothmajorbloodculturecriteriaandmajorechocardiographic criteria.ThefrequencyofmodifiedDukecriteriaisdetailedin

Table2.

Intravascularcatheterizationwasobservedinsevenpatients: three patients had a short-term central venous line and four patients hada hemodialysiscatheter. All catheterizationsites weretheinternaljugularvein.Thepresenceofaheartmurmur was detectedin21patients (80%).Themost common symp-tomswerechillsandfever.Themediandurationoffeverbefore diagnosis was 11 days (IQR;5–14 days). None of ourstudy patientshadJanewaylesionsand/orOsler’snodes.Splinter hem-orrhages wereobservedinonepatientandRoth’sspotintwo patients. Erythrocytesedimentation rate(ESR) was measured in22patients.ThemeanESR was67±32and80%of ESRs were 50mm/h. Transthoracic echocardiography (TTE) was performed in all patients, and 20 of them were further eval-uatedwithtransesophagealechocardiography(TEE).Embolic eventswereobservedinsixpatients(23%).Themajorsitefor embolic events was the brain (n=5). One patient developed septic arthritis andonepatient experiencedpulmonary septic emboli.Hematuriawasdetectedin9/25(36%)patients.

Overall, the study included five (19%) patients presenting withprostheticvalveendocarditisand21(81%)patients present-ingwithnativevalveendocarditis.Ofthe26patientspresenting withnon-HACEKGram-negativeIE,eleven(42%)hadmitral vegetation,five(19%)hadtricuspidvegetation,andsix(23%) hadaorticvegetation.Aorticdehiscencewasobservedinthree patients (12%). Oneof the 26 (4%)patients hadintracardiac device-associated(ICD)vegetations.Thelargestvegetationsize was20mmandthemediansizewas11mm(5–20mm). 3.2. Microbiologicaldata

The microbiological spectrum and drug resistance pattern ofnon-HACEK Gram-negativeIEinthe studypopulationare detailedinTable3

.Atleasttwobloodculturesetsweredrawnineachofthe26 patients.Allpatientshadatleastonepositivebloodcultureset (themeannumberofdrawnbloodculturesineachpatientwith apreliminarydiagnosisofIEwas5,andanaverageoffourof themgavepositiveresults).

3.3. Treatmentandoutcomes

IEdiagnosiswasmadeafteramedianofsevendays(IQR: 3–11days)followinghospitalization.Themediandurationofthe antibiotictherapywas42days(range3–75days).Feverusually resolvedwithinsevendaysofaneffectiveantibiotictherapy.

Cardiovascular surgical procedures were performed in 10 patients during hospitalization (valve replacement in nine

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M. Ertugrul Mer can et al. / Médecine et maladies infectieuses 49 (2019) 616–620 Table1

Demographical,clinical,andtreatmentfeaturesofGram-negativeendocarditiscases.

Paramètresdémographiques,cliniquesetthérapeutiquesdescasd’endocarditeinfectieuseàbacilleàGram-négatif.

Age,genderPredisposingconditions Pathogens Antibiotics Echocardiogramfindings SurgicalinterventionOutcome

36,M None Pseudomonasmendocinaa _Ceftazidime₊_amikacin _Mitral_vegetation _Yes _Alive

41,M None P.aeruginosa Ceftazidime+amikacin Mitralvegetation Yes Alive

51,M Aorticvalvereplacement,mitralvalvereplacement Salmonellaenteritidis Penicilling+gentamicin Mitralvegetation,heartfailure Yes Alive 52,F Mitralvalvereplacement Escherichiacoli Ofloxacin Mitralvegetation No Alive 58,M Atrialseptaldefect,ventricularseptaldefect,prostheticvalve Enterobactercloacae Imipenem/cilastatin Aorticvalvedehiscence,heartfailure No Alive 68,M Centralvenouscatheter,hemodialysis,immunocompromised E.coli Piperacillin-tazobactam Aorticvegetation,heartfailure No Alive 48,F Immunocompromised,livertransplant S.enteritidis Ciprofloxacin Mitralvegetation Yes Alive 67,F Immunocompromised,prostheticvalve Klebsiellapneumoniae Meropenem Aorticvegetation,heartfailure No Death 51,M Centralvenouscatheter,intracardiacdevice E.cloacae Piperacillin/tazobactam+cefepime Vegetationonintracardiacdevice,

heartfailure

No Alive

44,F None E.coli Ceftriaxone Mitralvegetation,heartfailure No Alive

45,M Previousendocarditis Pasteurellamultocida Amoxicillin Valvedehiscence No Alive 58,F Centralvenouscatheter K.pneumoniae Imipenem/cilastatin+amikacin Tricuspidvegetation No Alive

67,F Immunocompromised E.coli Amoxicillin Mitralvegetation No Alive

66,F None E.coli Ceftriaxone Aorticvegetation,heartfailure Yes Alive

33,F None K.pneumoniae Ceftriaxone+gentamicin Mitralvegetation No Death

36,M Centralvenouscatheter,hemodialysis P.aeruginosa Imipenem/cilastatin Tricuspidvegetation Yes Alive 84,F Centralvenouscatheter,hemodialysis E.coli Imipenem/cilastatin Tricuspidvegetation No Death 56,F Centralvenouscatheter,immunocompromised K.pneumoniae Ceftazidime+tigecycline Tricuspidvegetation Yes Alive 42,F Aorticvalvereplacement,mitralvalvereplacement K.pneumoniae Ceftriaxone+gentamicin+rifampicinAorticvegetation No Alive 59,F Centralvenouscatheter,hemodialysis P.aeruginosa Meropenem Tricuspidvegetation No Alive 64,M Post-coronaryangiography P.aeruginosaa _Ceftazidime₊_amikacin _Mitral_vegetation _No _Alive

61,M Post-coronaryangiography P.aeruginosaa _Ceftazidime₊_amikacin _Mitral_vegetation,_heart_failure _Yes _Death

28,F Post-coronaryangiography,aorticvalvereplacement P.aeruginosaa _Meropenem₊_amikacin _Aortic_valve_dehiscence,_heart_failure _Yes _Death

40,M Rheumaticheartvalvedisease S.enteritidis Ceftriaxone Aorticvegetation,heartfailure Yes Alive

47,F None E.coli Vancomycin+gentamicin Aorticvegetation No Alive

80,F Hemodialysis P.aeruginosa Notavailableb Mitralvegetation No Death

a_Previously_published_case_reports. b _The_patient_died_within₃_days.

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Table2

FrequencyofDukeCriteriaamong26patientspresentingwithnon-HACEK Gram-negativebacillusendocarditis.

FréquencedescritèresdeDukechez26patientsprésentantuneendocarditeà bacilleàGram-négatifnon-HACEK.

Criteria Frequencyn/n(%)

Majorbloodculturecriteria 26/26(100%)

Majorechocardiographiccriteria 26/26(100%)

Minorcriteria Predisposingfactor 19/26(73%) Fever 20/26(77%) Vascularsigns 6/26(23%) Immunologicalsigns 2/26(8%) Microbiologicalcriteria 0/26(0%) Table3

Microbiologicalspectrumanddrugresistancepatternofnon-HACEK Gram-negativeinfectiveendocarditisinthestudypopulation.

Spectred’activitémicrobiologiqueetrésistancedesendocarditesinfectieusesà bacilleàGram-négatifnon-HACEKdelapopulationàl’étude.

Bacteria Frequency,n(%) Drugresistancepattern

E.coli 7(26) 6/7pan-susceptible,1/7MDR P.aeruginosa 7(27) 7/8pan-susceptible,1/8MDR P.mendocina 1(3) K.pneumoniae 5(19) 2pan-susceptible,2MDR,1XDR S.enteritidis 3(10) Pan-susceptible E.cloacae 2(8) 2MDR P.multocida 1(4) Pan-susceptible MDR:multidrug-resistant;XDR:extensivelydrug-resistant.

patients andvalverepairinonepatient). Themedian timeto surgeryafterinitialdiagnosis of IEwas 24days (range5–54 days).Five(50%)of10patientswhounderwentsurgical proce-dureshadpositivevalve(vegetation)cultures(P.aeruginosain twopatients).Sixpatients(23%)diedduringthehospitalization period.Casefatality(2 of 10patients withmedical treatment onlyvs.4of16patientswithsurgicalandmedicaltreatment) didnotdiffersignificantly.

Sixhospitalswereabletoprovidethenumberofendocarditis cases.Amongallendocarditiscases,the proportionof Gram-negativeendocarditiswas1%.

4. Discussion

Endocarditisisachronicinfectionresultingfromthe inter-action between bacterial virulence (adherence, biofilm) and endocardial endothelial surface [10]. Non-HACEK Gram-negativebacteriadonotusuallycauseendocarditisduetotheir limitedabilitytoformbiofilmsandlowaffinitytoendocardial endothelium, except for Salmonella spp. [11]. A small num-berofstrainsofnon-HACEKGram-negativeagentscapableof formingbiofilms mightbethe causativeagents of endocardi-tiswith thehelp of predisposing factors(valveabnormalities andprostheticmaterials)that can facilitatethe persistence of the microorganism within the vegetation [12]. Pseudomonas speciescancausecommunity-acquiredandnosocomial endo-carditis [13]. In our study three P. aeruginosa endocarditis casesdevelopedafter coronaryangiographicintervention due

to contamination of the contrast medium in a tertiary hos-pital. Salmonella species are also rare pathogens responsible forinfectiveendocarditis[14].Whileenvironmentalpathogens arepan-susceptibletoantimicrobials,Klebsiellaendocarditisis associatedwithahigherriskofdrugresistance.

The most prominent risk factor for non-HACEK Gram-negative IE observed in our study was determined by the presence of an intravascular catheter, as recently reported

[5–7]. Permanent central venous catheters (e.g., hemodialy-sis catheters)are associated with ahigher risk of developing Gram-negativeendocarditis,especiallyinimmunocompromised patients.Previousstudiesreportedintravenousdruguseasthe most prevalentriskfactorfor non-HACEK Gram-negativeIE

[7,8].Intravenousdrugusewasnotobservedinourstudy pop-ulation. Onthe basisof underlyingvalvediseases(rheumatic valvedisease,degenerativevalvedisease,andthepresenceof prosthetic valve), the predisposing condition distribution was similartotheresultsofpreviousstudies[5–7].

The dynamic epidemiological changes in both host- and pathogen-related factorsarenewchallenges forclinicians. IE patientsarenowolderandhavemorecomorbidconditions[15]. AccordingtotheInternationalCollaborationon Endocarditis-ProspectiveCohortStudy(ICE-PCS)results,healthcarecontact andimplantationofendovasculardevicesareprimaryrisk fac-torsfornon-HACEKGram-negativeIE[5,6].Seventeenpatients in our study had underlying diseases that related to at least one surgical (valve replacement, catheterization) or medical (chemotherapy,hemodialysis)intervention.

Thecasefatalityobservedinourstudywassimilarbetween patients who did or did not undergo surgical therapy (20% vs.25%).Thisresultsuggeststhatsurgicaltreatmentmaynot alwaysbeanabsoluteindicationasmentionedinprevious stud-ies[5,7].Ourin-hospitalcasefatalitywassimilartotheresults ofpreviouslarge-scalestudies[5,7].

5. Conclusion

Cliniciansmayencounternon-HACEKGram-negative infec-tiveendocarditis,mostlyinmedicalwardsasmanyintravascular interventionsareperformedandaselderlypatientsaremanaged inthosewards.

Disclosureofinterest

Theauthorsdeclarethattheyhavenocompetinginterest.

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